Substituted pyrrolo[3,2-d]pyrimidine derivatives

ABSTRACT

A compound having GSK-3 inhibitory activity. 
     
       
         
         
             
             
         
       
     
     A 1  and A 3  are a single bond, an aliphatic hydrocarbon group; A 2  and A 4  are a single bond, CO, COO, CONR, O, OCO, NR, NRCO, NRCOO, etc.; G 1  is a single bond, an aliphatic hydrocarbon, aromatic hydrocarbon, heterocyclic; G 2  is H, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aromatic hydrocarbon, heterocyclic; A 5  is a single bond, NR; R 2  is H, halogen, an aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; A 6  is a single bond, NR, CO, NRCO, NRCONR, CONR, COO, O, etc.; R 3  is H, halogen, nitro, saturated aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; and R 3  may be a trimethylsilyl, formyl, acyl, carboxyl, alkoxylcarbonyl, carbamoyl, alkylcarbamoyl, or cyano group when A 6  is CR═CR or C≡C, wherein R is H or an lower aliphatic hydrocarbon group.

This application claims benefit to Provisional Application No.60/499,071 filed Sep. 2, 2003 and Provisional App. No. 60/560,013 filedApr. 7, 2004.

TECHNICAL FIELD

The present invention relates to novel pyrrolopyrimidinone derivativesthat have an action inhibiting glycogen synthase kinase-3 (GSK-3). Moreparticularly, the invention relates to novel pyrrolo[3,2-d]pyrimidinonederivatives useful as pharmaceutical agents for treating and/orpreventing disorders mediated by GSK-3 activity, particularly, impairedglucose tolerance, type I diabetes, type II diabetes, diabeticcomplications (retinopathy, nephropathy, neuropathy or great vesselhindrance), Alzheimer's disease, neurodegenerative diseases (AIDSencephalophy, Huntington's disease, Parkinson's disease, amyotrophiclateral sclerosis or multiple sclerosis), bipolar affective disorder(manic depressive psychosis), traumatic cerebrospinal injury, epilepsy,obesity, atherosclerosis, hypertension, polycystic ovary syndrome,syndrome X, alopecia, inflammatory diseases (arthrosis deformans,rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn'sdisease, sepsis or systemic inflammatory response syndrome), cancer andimmunodeficiency.

BACKGROUND ART

GSK-3 is a serine/threonine protein kinase. Two isoforms, i.e., α and β,which are encoded by distinct genes, have been identified (see TrendsBiochem. Sci., 1991, Vol. 16, p. 177).

Both GSK-3 isoforms have a monomeric structure and are constitutivelyactive in resting cells. GSK-3 was originally identified as a kinasethat inhibits glycogen synthase by direct phosphorylation (see Eur. J.Biochem., 1980, Vol. 107, p. 519). Upon insulin activation, GSK-3 isinactivated, thereby allowing the activation of glycogen synthase andpossibly other insulin-dependent events, such as glucose transport.Also, it has been known that GSK-3 activity is inactivated by othergrowth factors, such as IGF-1 or FGF, through signaling from receptortyrosine kinases (see Biochem. J., UK, 1993, Vol. 294, p. 625; Biochem.J., UK, 1994, Vol. 303, p. 21; Biochem. J., UK, 1994, Vol. 303, p. 27).

GSK-3 inhibitors are useful in the treatment of disorders that aremediated by GSK-3 activity. In addition, inhibition of GSK-3 mimics theactivation of growth factor signaling pathways and consequently GSK-3inhibitors are useful in the treatment of diseases in which suchpathways are inactive. Examples of diseases that can be treated withGSK-3 inhibitors are described below.

Type I diabetes is induced due to autoimmune destruction of β cells aspancreatic insulin production cells, resulting in deficiency of insulin.From this, it is necessary for a type I diabetic patient to routinely beadministered insulin for maintaining life. However, in current insulintherapy, strict control of the blood glucose levels like the ability ofnormal β cells cannot be reproduced. Thus, type I diabetes is liable toinduce diabetic complications such as retinopathy, nephropathy,neuropathy, great vessels hindrance or the like.

Type II diabetes is a multifactorial disease. Hyperglycemia is due toinsulin resistance in the liver, skeletal muscle and lipid tissuescoupled with inadequate or defective secretion of insulin frompancreatic islets. As a result, diabetic complications such asretinopathy, nephropathy, neuropathy, or great vessels hindrance areinduced. Skeletal muscle is the major site for insulin-stimulatedglucose uptake, and glucose removed from the circulation is eithermetabolized through glycolysis and the TCA cycle or stored as glycogen.Muscle glycogen deposition plays a very important role in glucosehomeostasis, and Type II diabetic subjects have defective muscleglycogen storage. GSK-3, which is known to phosphorylate glycogensynthase, inhibits the accumulation of glycogen in peripheral tissuesand lowers the reactivity of insulin, leading to an increase in bloodlevel of glucose.

Recently, it has been reported that the expression of GSK-3 isstimulated in skeletal muscles of type II diabetic patients, and theGSK-3α activity and insulin in skeletal muscles are inversely correlated(see Diabetes, USA, 2000, Vol. 49, p. 263). Where GSK-3β and activeGSK-3β variants (S9A, S9E) are overexpressed in HEK-293 cells, the GSKactivity is inhibited (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93,p. 10228). In CHO cells in which insulin receptor and insulin receptorsubstrate 1 (IRS-1) are expressed, overexpression of GSK-3β brings abouta decrease in the insulin activity (see 8: Proc. Natl. Acad. Sci., USA,1997, Vol. 94, 9660). Recent research carried out using C57BL/6J micewith pyknic type diabetes has clearly shown that GSK-3 activitystimulation and insulin resistance are correlated to the progress oftype II diabetes (see Diabetes, USA, 1999, Vol. 48, p. 1662).

Conventionally, lithium salts have been known to have inhibitory effectsof GSK-3 activity (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p.8455). It has been reported that the therapy using the lithium saltslowers glucose levels in both type I and II diabetic patients, therebyalleviating the severity of the disease (see Biol. Trace Elements Res.,1997, Vol. 60, p. 131). However, lithium salts have also been found toexhibit various side effects on molecular targets other than GSK-3.

From the findings described above, it can be concluded that GSK-3inhibitors are effective therapeutics for the treatment of impairedglucose tolerance, type I diabetes, type II diabetes and complicationsthereof.

It is also suggested that GSK-3 is associated with progress ofAlzheimer's disease. The characteristic pathological features ofAlzheimer's disease are senile plaques due to agglomeration of amyloidbeta (Aβ) peptide and the formation of intracellular neurofibrillarytangles, leading to a large quantity of neuronal cell death, resultingin dementia. It is believed that GSK-3 involves abnormal phosphorylationof tau protein, which causes a neurofibrillary change in the course ofprogress of Alzheimer's disease (see Acta Neuropathol., 2002, Vol. 103,p. 91). Also, it has been found that GSK-3 inhibitors can preventneuronal cell death (see J. Neurochem., 2001, Vol. 77, p. 94).Therefore, it is believed that the application of GSK-3 inhibitors toAlzheimer's disease can delay the progress of the disease. To date,therapeutic agents for Alzheimer's disease have mainly been used inconjunction with allopathy (see Expert Opin. Pharmacother., 1999, Vol.1, p. 121). However, there is no known pharmaceutical agent that iseffective in preventing neuronal cell death and delaying the onset orprogress of Alzheimer's disease. These findings imply that GSK-3inhibitors are effective pharmaceutical agents in alleviating theseverity of Alzheimer's dementia.

There is a report that GSK-3 inhibitors suppress neuronal cell death,specifically, neuronal cell death due to overexcitement through glutamicacid (see Proc. Natl. Acad. Sci., USA, 1998, Vol. 95, p. 2642; J.Neurochem., 2001, Vol. 77, p. 94). This suggests that GSK-3 inhibitorsare possibly useful in the treatment of bipolar affective disorder suchas manic depressive psychosis, epilepsy or other degenerative braininjury or neurodegenerative diseases. Examples of the neurodegenerativedisease include in addition to the Alzheimer's disease, AIDSencephalopathy, Huntington's disease, Parkinson's disease, amyotrophiclateral sclerosis, multiple sclerosis, Pick's disease, progressivesupranuclear palsy and so on. Also, overexcitement through glutamic acidis presumably a principal cause of brain dysfunction in stroke,including cerebral infarction, intracerebral hemorrhage and subarachnoidhemorrhage, traumatic cerebrospinal injury, bacteria/virus infectiousdisease, and GSK-3 inhibitors are expected to be effectively used in thetreatment of these diseases. All of such diseases accompany neuronaldeath. Currently, no therapeutic agents for effectively suppressingneuronal death are available. Therefore, GSK-3 inhibitors are believedto become potentially effective pharmaceutical agents for the treatmentof various kinds of neurodegenerative diseases, dipolar affectivedisorders (manic-depressive psychosis), epilepsy, stroke, traumaticcerebrospinal injury, and the like.

Several in vitro research results have led to a report that Wint10Bpotently suppresses the differentiation of preadipocytes to mature fatcells (see Science, 2000, Vol. 289, p. 950). GSK-3 specific inhibitorsmimic Wint10B signaling in preadipocytes, that is, GSK-3 specificinhibitors stabilize free β-catenin in cytoplasm and suppress theinduction of C/EBPα and PPARγ, thereby suppressing the formation of fat(see J. Biol. Chem, 2002, Vol. 277, p. 30998). GSK-3 inhibitors aretherefore potentially useful as effective pharmaceutical compositionsfor treating obesity.

Also, β-catenin has been known to be a GSK-3 substrate in vivo. Afterphosphorylation by GSK-3, β-catenin is subjected to proteosome-dependentdegradation (see EMBO J., 1998, Vol. 17, p. 1371). Meanwhile, transientβ-catenin stabilization may lead to increase hair development (see Cell,1998, Vol. 95, p. 605). Consequently, GSK-3 inhibitors are believed tobe a useful medicament for the treatment of alopecia.

Further, research into GSK-3β knock out mouse-derived fibroblastsimplies that GSK-3β regulates the activity of transcription factor NFκBto be at a positive level (see Nature, 2000, Vol. 406, p. 86). NFκB isin charge of cell responsiveness to numerous inflammatory stimuli. Thus,GSK-3 inhibitors may have beneficial effects in the treatment ofinflammatory diseases such as arthrosis deformans, rheumatism, atopicdermatitis, psoriasis, ulcerative colitis, Crohn's Disease, sepsis, orsystemic inflammatory response syndrome, by adjusting the NFκB activityto be at a negative level.

A transcription factor NF-AT is dephosphorylated by calcineurine andincreases immunosuppressive response (see Science, 1997, Vol. 275, p.1930). Conversely, GSK-3 phosphorylates NF-AT and transports the samefrom nuclei, thereby suppressing the expression of initial immuneresponse gene. Thus, GSK-3 inhibitors could be useful to immunityactivation for cancer immunotherapy.

Examples of materials that have conventionally been known to have GSK-3inhibiting activity include hymenialdisine derivatives (see Chemistry &Biology, 2000, Vol. 7, p. 51, and WO01/41768 pamphlet), maleiimidederivatives (see Chemistry & Biology, 2000, Vol. 7, p. 793), paullonederivatives (see Eur. J. Biochem., 2000, Vol. 267, p. 5983 andWO01/60374 Pamphlet), purine derivatives (see WO98/16528 Pamphlet),pyrimidine and pyridine derivatives (see WO99/65897 Pamphlet),hydroxyflavone derivatives (see WO00/17184 Pamphlet), pyrimidonederivatives (see WO00/18758, WO01/70683, WO01/70729, WO01/70728,WO01/70727, WO01/70726, and WO01/70725 Pamphlets), pyrrole-2,5-dionederivatives (see WO00/21927 and WO01/74771 Pamphlets),diamino-1,2,4-triazolecarboxylic acid derivatives (see WO01/09106Pamphlet), pyrazine derivatives (see WO01/44206 Pamphlet), bicyclicinhibitor (see WO01/44246 Pamphlet), indirubine derivatives (seeWO01/37819 Pamphlet), carboxamide derivatives (see WO01/42224 Pamphlet),peptide inhibitors (see WO01/49709 Pamphlet), 2,4-diaminothiazolederivatives (see WO01/56567 Pamphlet), thiadiazolidindione derivatives(see WO01/85685 Pamphlet), aromatic amide derivatives (see WO01/81345Pamphlet), and so on.

Also, the claims of WO02/085909 Pamphlet show a wide variety ofcompounds including pyrrolopyrimidine derivatives. However, bicyclicpyrrolopyrimidine derivatives actually synthesized are those havingcyano groups at the 7-position of pyrrolopyrimidine ring and limitedvariety of substituents at other substitutable positions. In addition,while it discloses a method for assaying inhibitory activity of GSK-3etc., it is silent about which compounds have such activities.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel compounds whichare specific to and capable of strongly inhibiting the activity of GSK-3while being clinically applicable, and pharmaceutical compositions asGSK-3 inhibitors using them as effective ingredients.

Also, another object of the present invention is to provide an agent fortreating or preventing a GSK-3-mediated disease.

Further, still another object of the present invention is to provide amethod for treating a GSK-3-mediated disease.

The present inventors studied the above objects and consequently reachedthe following inventions.

Namely, the present invention provides a compound represented by thefollowing formula (I) or a pharmaceutically acceptable salt thereof.

in the formula (I),

A¹ represents a single bond or represents a divalent acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atombonded to A¹ with A² on the same or different carbon atom;

A² represents a single bond or represents a group that links A¹ with G¹in the form of

A¹ —C(═O)-G¹,

A¹-C(═O)—O-G¹,

A¹-C(═O)—NR¹⁰¹-G¹,

A¹-C(═S)—NR¹⁰²-G¹,

A¹-C(═NR¹⁰³)-G¹,

A¹-O-G¹,

A¹-OC(═O)-G¹,

A¹-NR¹⁰⁴-G¹,

A¹-NR¹⁰⁵—C(═O)-G¹,

A¹-NR¹⁰⁶—S(═O)₂-G¹,

A¹-NR¹⁰⁷—C(═O)—O-G¹,

A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹,

A¹-NR¹¹⁰C(═S)-G¹,

A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹,

A¹-S-G¹,

A¹-S(═O)-G¹,

A¹-S(═O)₂-G¹,

A¹-S(═O)₂—NR¹¹³-G¹,

A¹-CR¹¹⁴═CH-G¹,

A¹-CR¹¹⁵═CF-G¹,

A¹-CH═CR¹¹⁶-G¹, or

A¹-CF═CR¹¹⁷-G¹;

G¹ represents a single bond or represents a divalent group which isobtainable by removing two hydrogen atoms from any one of an optionallysubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, anoptionally substituted aromatic hydrocarbon having 6 to 14 carbon atoms,and an optionally substituted heterocyclic compound having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring.

A³ represents a single bond or represents an optionally substitutedaliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹with A⁴ on the same or different carbon atom;

A⁴ represents a single bond or represents a group that links A³ with G²in the form of

A³ —C(═O)-G²,

A³-C(═O)—O-G²,

A³-C(═O)—NR¹²¹-G²,

A³-C(═S)—NR¹²²-G²,

A³-C(═NR¹²³)-G²,

A³-O-G²,

A³-O—C(═O)-G²,

A³-NR¹²⁴-G²,

A³-NR¹²⁵—C(═O)-G²,

A³-NR¹²⁶—S(═O)₂-G²,

A³-NR¹²⁷—C(═O)—O-G²,

A³-NR¹²⁸—C(═O)—NR¹²⁹-G²,

A³-NR¹³⁰—C(═S)-G²,

A³-NR¹³¹—C(═S)—NR¹³²-G²,

A³-S-G²,

A³-S(═O)-G²,

A³-S(═O)₂-G²,

A³-S(═O)₂—NR¹³³-G² or

A³-S(═O)₂—O-G²;

G² represents a hydrogen atom, an optionally substituted aliphatichydrocarbon group having 1 to 10 carbon atoms, an optionally substitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, oran optionally substituted heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring;

A⁵ represents a single bond or —NR²⁰¹—;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an optionally substituted aliphatichydrocarbon group having 1 to 10 carbon atoms, an optionally substitutedalicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, oran optionally substituted heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring;

A⁶ represents a single bond or represents a group that links R³ with acarbon atom of a pyrrole ring to which A⁶ is bonded, in the form of

R³—NR³⁰¹-pyrrole ring,

R³—C(═O)-pyrrole ring,

R³—NR³⁰²—C(═O)-pyrrole ring,

R³—NR³⁰³—C(═S)-pyrrole ring,

R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring,

R³—C(═O)—NR³⁰⁶-pyrrole ring,

R³—NR³⁰⁷—CH═N-pyrrole ring,

R³—C(═O)—O-pyrrole ring,

R³—O—C(═O)-pyrrole ring,

R³—O-pyrrole ring,

R³—S-pyrrole ring,

R³—S(═O)-pyrrole ring,

R³—S(═O)₂-pyrrole ring,

R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring,

R³—C≡C-pyrrole ring, or

R³—S(═O)₂—C≡C-pyrrole ring;

R³ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,an iodine atom, a nitro group, an optionally substituted saturatedaliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionallysubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, anoptionally substituted aromatic hydrocarbon group having 6 to 14 carbonatoms, or an optionally substituted heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring;

A⁶-R³ may be a combination wherein A⁶ represents a group that links acarbon atom of a pyrrole ring to which A⁶ is bonded, with R³ in the formof R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring, and R³ representsa trimethylsilyl group, a formyl group, an optionally substituted C₂-C₇acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoylgroup, an optionally substituted C₂-C₇ alkylcarbamoyl group, or a cyanogroup;

R¹⁰¹˜R¹¹⁷, R¹²¹˜R¹³³, R²⁰¹ and R³⁰¹˜R³⁰⁹ are each independently ahydrogen atom or an aliphatic hydrocarbon group having 1 to 4 carbonatoms.

However, when both A¹ and A³ represent acyclic alphatic hydrocarbongroups, at least one of A² or G¹ is not a single bond.

In addition, the present invention provides a pharmaceutical compositioncomprising the compound or a pharmaceutically acceptable salt thereofrepresented by the formula (I); and a pharmaceutically acceptablecarrier.

Further, the present invention provides a GSK-3 inhibitor comprising thecompound or a pharmaceutically acceptable salt thereof represented bythe formula (I) as an effective ingredient.

Furthermore, the present invention provides an agent for treating orpreventing a GSK-3-mediated disease, comprising the compound or apharmaceutically acceptable salt thereof represented by the formula (I)as an effective ingredient.

Furthermore, the present invention provides a method for treating aGSK-3-mediated disease, comprising a step of injecting the compound or apharmaceutically acceptable salt thereof represented by the formula (I)in treatment valid amount to a patient.

Note that, in A¹-G² portion in the formula (1), there also exists a casewhere different combinations consequently represent the same substituentaccording to the combination of A¹, A², G¹, A³, A⁴, and G², andcombinations containing also substituents of them where they may havesubstituents. However, the scope of the present invention will notbecome clear due to this.

Note that the corresponding pyrimidine-thione derivative can be derivedfrom the compound represented by the formula (I) of the presentinvention through the pyrrolopyrimidine derivative represented by thefollowing formula (II).

in formula (I), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ are as definedin the formula (I); and X¹ is a chlorine atom, a bromine atom, an iodineatom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, a C₁-C₈alkyl group, or a C₁-C₈ arylsulfonyloxy group).

Still further, the present invention is a compound represented by thefollowing formula (Ic) which can be used as the manufacture intermediateof the pyrrolopyrimidinone derivative represented by the formula (I).

in formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are asdefined in the formula (I); and Q represents an optionally substituted aC₂-C₁₀ acyl group, an optionally substituted C₂-C₁₀ alkoxymethyl groupor an optionally substituted benzyl group.

BEST MODE FOR WORKING THE INVENTION

The “acyclic aliphatic hydrocarbon group” in the present descriptioncontains a straight or branched acyclic aliphatic hydrocarbon group. Itmay be saturated so far as it is the acyclic aliphatic hydrocarbon groupas well and may have one or more double bonds or triple bonds in achemically possible range.

The “alkyl group” in the present description represents a straight orbranched saturated acyclic aliphatic hydrocarbon group, for examplemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl,isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, t-pentyl, or isohexyl.

The “pyridyl group” in the present description contains N-oxide thereofas well.

The term “cycloalkyl group” in the present description means a saturatedalicyclic hydrocarbon group, for example cyclopropyl, cyclobutyl, orcyclohexyl.

The term “heterocyclic” in the present description is not particularlylimited so far as it can chemically stably exist if it is monocyclic totricyclic having 1 to 4 atoms selected from among a group consisting ofan oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, butpreferably monocyclic or bicyclic having carbon atoms not more than 9containing 1 to 3, preferably 1 or 2 atoms selected from among a groupconsisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in thering.

In the formula (I), A¹ represents a single bond or represents a divalentacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms thatlinks a nitrogen atom bonded to A¹ with A² on the same or differentcarbon atoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms in A¹ include divalent groups obtainable by removing two hydrogenatoms from methane, ethane, propane, butane, 2-methylpropane, pentane,2-methylbutane, 2,2-dimethylpropane, hexane, 2-methylpentane,3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane and2,2,3-trimethylpropane.

Examples of suitable A¹ include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂—)₅—, —(CH₂)₆—, —CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—,—C(CH₃)₂CH₂—, —CH(CH₃)(CH₂)₂—, —CH₂CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)CH₂—,—CH(CH₃)CH₂CH(CH₃)—, —CH₂C(CH₃)₂CH₂—, —CH(CH₃)C(CH₃)₂CH₂—,—CH(CH₂CH₃)(CH₂)₂—, —CH₂CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH(CH₃)CH₂—,—CH(CH₃)CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH₂CH(CH₃)—, —CH(CH₃)(CH₂)₃—,—CH₂CH(CH₃)(CH₂)₂—, —CH(CH₃)CH(CH₃)(CH₂)₂—, —CH(CH₃)CH₂CH(CH₃)CH₂—,—CH₂CH(CH₃)CH(CH₃)CH₂—, —CH₂C(CH₃)₂ (CH₂)₂—, —CH(CH₃)C(CH₃)₂CH₂—,—CH(CH₂CH₃)(CH₂)₃—, —CH₂CH(CH₂CH₃)(CH₂)₂—, —CH(CH₃)(CH₂)₄—,—CH₂CH(CH₃)(CH₂)₃—, and —(CH₂)₂CH(CH₃)(CH₂)₂—. Examples of preferred A¹include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—,—CH(CH₃)CH(CH₃)—, —CH(CH₃)(CH₂)₂—, —CH₂CH(CH₃)CH₂—, and—CH(CH₃)CH(CH₃)CH₂—. More preferred examples of A¹ include —CH₂—,—(CH₂)₂—, and —(CH₂)₃—. As more preferable examples of A¹, —(CH₂)₂— maybe mentioned.

In the formula (I), A² represents a single bond or represents a groupthat links A¹ and G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)—O-G¹,A¹-C(═O)—NR¹⁰¹-G¹, A¹-C(═S)—NR¹⁰²-G¹, A¹-C(═NR¹⁰³)-G¹, A¹-O-G¹,A¹-O—C(═O)-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁶—S(═O)₂-G¹,A¹-NR¹⁰⁷—C(═O)—O-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹-NR¹¹⁰—C(═S)-G¹,A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, A¹—S-G¹, A¹-S(═O)-G¹, A¹-S(═O)₂-G¹,A¹-S(═O)₂—NR¹¹³-G¹, A¹-CR¹¹⁴═CH-G¹, A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹ orA¹-CF═CR¹¹⁷-G¹ (R¹⁰¹˜R¹¹⁷ are independently a hydrogen atom or a acyclicaliphatic hydrocarbon group having 1 to 4 carbon atoms).

When A¹ and G¹ are linked to each other in the form ofA¹-C(═O)—NR¹⁰¹-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹⁰¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, cyclopropylmethyl, 2-propenyl, 2-butenyl, 3-butenyl,2-propynyl, 2-butynyl and 3-butynyl group. The C₁-C₄ acyclic aliphatichydrocarbon group may also be substituted with one or more substituentsselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, a methoxy group, anethoxy group, an oxo group, a cyano group, a carboxyl group, a carbamoylgroup, an amino group, a sulfo group, and a phenyl group. Examples ofpreferred R¹⁰¹ include a hydrogen atom, methyl, ethyl, and propyl group.Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-C(═S)—NR¹⁰²-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹⁰² include the same as those selected as the examples of R¹⁰¹.Examples of preferred R¹⁰² include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-C(═NR¹⁰³)-G¹,examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰³ include thesame as those selected as the examples of R¹⁰¹. Examples of preferredR¹⁰³ include a hydrogen atom, methyl, ethyl, and propyl group.Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁴-G¹,examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁴ include thesame as those selected as the examples of R¹⁰¹. Examples of preferredR¹⁰⁴ include a hydrogen atom, methyl, ethyl, and propyl group.Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹⁰⁵—C(═O)-G¹, examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹⁰⁵ include the same as those selected as the examples ofR¹⁰¹. Examples of preferred R¹⁰⁵ include a hydrogen atom, methyl, ethyl,and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹⁰⁶—S(═O)₂-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹⁰⁶ include the same as those selected as the examples of R¹⁰¹.Examples of preferred R¹⁰⁶ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹⁰⁷—C(═O)—O-G¹, examples of the C₁-C₄ aliphatic hydrocarbon groupof R¹⁰⁷ include the same as those selected as the examples of R¹⁰¹.Examples of preferred R¹⁰⁷ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹⁰⁸—C(═O)NR¹⁰⁹-G¹, examples of such preferred C₁-C₄ aliphatichydrocarbon group of R¹⁰⁸ and R¹⁰⁹ include the same as those selected asthe examples of R¹⁰¹. Examples of preferred R¹⁰⁸ and R¹⁰⁹ include ahydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogenatom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹¹⁰—C(═S)-G¹, examples of such preferred C₁-C₄ aliphatichydrocarbon group of R¹¹⁰ include the same as those selected as theexamples of R¹⁰¹. Examples of preferred R¹¹⁰ include a hydrogen atom,methyl, ethyl, and propyl group. Particularly, a hydrogen atom ispreferred.

When A¹ and G¹ are linked to each other in the form ofA¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, examples of the C₁-C₄ aliphatic hydrocarbongroup of R¹¹¹ and R¹¹² include the same as those selected as theexamples of R¹⁰¹. Examples of preferred R¹¹¹ and R¹¹² include a hydrogenatom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom ispreferred.

When A¹ and G¹ are linked to each other in the form ofA¹-S(═O)₂—NR¹¹³-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹¹³ include the same as those selected as the examples of R¹⁰¹.Examples of preferred R¹¹³ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form ofA¹-CR¹¹⁴═CR¹¹⁵-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹¹⁴ and R¹¹⁵ include the same as those selected as the examples ofR¹⁰¹. Examples of preferred R¹¹⁴ and R¹¹⁵ include a hydrogen atom,methyl, ethyl, and propyl group. Particularly, a hydrogen atom ispreferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹,examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include thesame as those selected as the examples of R¹⁰¹. Examples of preferredR¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group.Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹,examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include thesame as those selected as the examples of R¹⁰¹. Examples of preferredR¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group.Particularly, a hydrogen atom is preferred.

Examples of preferred A² include groups that link A¹ and G¹ in the formof A¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-O-G¹, A¹-NR¹⁰⁴-G¹,A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹-NR¹¹⁰—C(═S)-G¹ andA¹-NR¹¹¹—C(═S)NR¹¹²-G¹, especially preferably in the form ofA¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹,A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, and A¹-NR¹¹⁰—C(═S)-G¹. Among them, examples ofmore preferred A² include groups that link A¹ and G¹ in the form ofA¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, and A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹. Here,forms of linkage exemplified as preferred and more preferred A² arepreferably combined with structures in which A¹ exists in the form of—(CH₂)₂— or —(CH₂)₃— in the formula (I).

In the formula (I), A³ represents a single bond or represents anoptionally substituted divalent aliphatic hydrocarbon group having 1 to10 carbon atoms that links G¹ and A⁴ on the same or different carbonatoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 10carbon atoms of A³ include, in addition to the same as those selected asthe examples of A¹, —CH═CH—, —C(CH₃)═CH—, —C(CH₃)═C(CH₃)—,—C(CH₂CH₃)═CH—, —C(CH₂CH₃)═C(CH₃)—, —C(CH₂CH₃)═C(CH₂CH₃)—,—C(CH₂CH₂CH₃)═CH—, —C(CH₂CH₂CH₃)═C(CH₃)—, —CH═CHCH₂—, —C(CH₃)═CHCH₂—,—CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —C(CH₃)═C(CH₃)CH₂—, —C(CH₃)═CHCH(CH₃)—,—C(CH₃)═C(CH₃)CH(CH₃)—, —C(CH₃)═CHC(CH₃)₂—, —C(CH₂CH₃)═CHCH₂—,—CH═C(CH₂CH₃)CH₂—, —CH═CHCH(CH₂CH₃)—, —C(CH₂CH₃)═C(CH₃)CH₂—,—C(CH₂CH₃)═CHCH(CH₃)—, —C(CH₃)═C(CH₂CH₃)CH₂—, —CH═C(CH₂CH₃)CH(CH₃)—,—CH═CHCH(CH₂CH₃)—, —C(CH₃)═CHCH(CH₂CH₃)—, —CH═C(CH₃)CH(CH₂CH₃)—,—CH═CH(CH₂)₂—, —C(CH₃)═CH(CH₂)₂—, —CH═C(CH₃)(CH₂)₂—, —CH═CHC(CH₃)CH₂—,—C H═CHCH₂CH(CH₃)—, —C(CH₃)═C(CH₃)(CH₂)₂—, —C(CH₃)═CHCH(CH₃)CH₂—,—C(CH₃)═CHCH₂CH(CH₃)—, —CH₂CH═CHCH₂—, —CH(CH₃)CH═CHCH₂—,—CH₂C(CH₃)═CHCH₂—, —CH(CH₃)C(CH₃)═CHCH₂—, —CH(CH₃)CH═CHCH(CH₃)—,—CH(CH₃)CH═C(CH₃)CH₂—, —CH₂C(CH₃)═C(CH₃)CH₂—, —CH(CH₂CH₃)CH═CHCH₂—, and—CH₂C(CH₂CH₃)═CHCH₂—.

Substituents of divalent substituted aliphatic hydrocarbon group having1 to 10 carbon atoms of A³ include a hydrocarbon group having 1 to 6carbon atoms, an alicyclic hydrocarbon group having 3 to 6 carbon atoms,a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a phenoxygroup, an amino group, or an alkyl amino group having 1 to 6 carbonatoms.

Examples of such preferred A³ include a single bond, —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —CH(CH₃)(CH₂)₂—,—CH═CH— and —CH═CHCH₂—. Further, examples of more preferred A³ include asingle bond, —CH₂—, —(CH₂)₂— and —(CH₂)₃—. The same applies when A³ issubstituted, but a single bond is excluded.

In the formula (I), A⁴ represents a single bond or represents a groupthat links A³ and G² in the form of A³-C(═O)-G², A³-C(═O)—O-G²,A³-C(═O)—NR¹²¹-G², A³-C(═S)—NR¹²²-G², A³-C(═NR¹²³)-G², A³-O-G²,A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G²,A³-NR¹²⁷—C(═O)—O-G², A³-NR¹²⁸—C(═O)—NR¹²⁹-G², A³-NR¹³⁰—C(═S)-G²,A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O)-G², A³-S(═O)₂-G²,A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G² (in which R¹²¹ through R¹³³ areeach independently a hydrogen atom or a acyclic aliphatic hydrocarbongroup having 1 to 4 carbon atoms).

When A³ and G² are linked to each other in the form ofA³-C(═O)—NR¹²¹-G², examples the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹²¹ include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹²¹ include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-C(═S)—NR¹²²-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹²² include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹²² include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-C(═NR¹²³)-G²,examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²³include the same as those selected as the examples of R¹⁰¹ in A².Examples of preferred R¹²³ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁴-G²,examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁴include the same as those selected as the examples of R¹⁰¹ in A².Examples of preferred R¹²⁴ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹²⁵—C(═O)-G², examples of the C₁-C₄ aliphatic hydrocarbon group ofR¹²⁵ include the same as those selected as the examples of R¹⁰¹ in A².Examples of preferred R¹²⁵ include a hydrogen atom, methyl, ethyl, andpropyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹²⁶—S(═O)₂-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹²⁶ include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹²⁶ include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹²⁷—C(═O)—O-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹²⁷ include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹²⁷ include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹²⁸—C(═O)—NR¹²⁹-G², examples of the C₁-C₄ aliphatic hydrocarbongroup of R¹²⁸ and R¹²⁹ include the same as those selected as theexamples of R¹⁰¹ in A². Examples of preferred R¹²⁸ and R¹²⁹ include ahydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogenatom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹³⁰—C(═S)-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹³⁰ include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹³⁰ include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-NR¹³¹—C(═S)—NR¹³²-G², examples of the C₁-C₄ acyclic aliphatichydrocarbon group of R¹³¹ and R¹³² include the same as those selected asthe examples of R¹⁰¹ in A². Examples of preferred R¹³¹ and R¹³² includea hydrogen atom, methyl, ethyl, and propyl group. Particularly, ahydrogen atom is preferred.

When A³ and G² are linked to each other in the form ofA³-S(═O)₂—NR¹³³-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbongroup of R¹³³ include the same as those selected as the examples of R¹⁰¹in A². Examples of preferred R¹³³ include a hydrogen atom, methyl,ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

Examples of such A⁴ include a single bond and a group that links A³ andG² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³-C(═O)—NR¹²¹-G²,A³-O-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-S(═O)₂-G² or A³-S(═O)₂—O-G².

In the formula (I), G¹ represents a single bond or a divalent groupobtainable by removing two hydrogen atoms from any of groups consistingof a substituted or unsubstituted alicyclic hydrocarbon group having 3to 10 carbon atoms, a substituted or unsubstituted aromatic hydrocarbongroup having 6 to 14 carbon atoms, and a heterocyclic compound having 1to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on its substituted or unsubstitutedring.

In the formula (I), when G¹ represents a substituted or unsubstituteddivalent alicyclic hydrocarbon group having 3 to 10 carbon atoms,examples of the alicyclic hydrocarbon group having 3 to 10 carbon atomsinclude cyclopropane, cyclobutane, cyclopentane, cyclopentene,cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane andbicyclo[2.2.2]octane. Examples of such preferred C₃-C₁₀ alicyclichydrocarbon of G¹ include monocyclic alicyclic hydrocarbon group having3 to 6 carbon atoms such as cyclopropane, cyclopentane, cyclohexane andthe like.

Examples of the substituent for the substituted alicyclic hydrocarbongroup having 3 to 10 carbon atoms of G¹ include: a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a hydroxy group, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy,isohexyloxy, 2-methyl-pentyloxy, 1-ethylbutoxy, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy,cyclopropylethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy oranother C₁-C₇ alkoxy group consisting of a straight or branched alkyl,cycloalkyl and oxy group, ethylene dioxy or another C₁-C₄ alkylenedioxygroup, phenoxy, 1-naphthoxy and 2-naphthoxy or another C₆-C₁₀ aryloxygroup, benzyloxy, α-phenethyloxy, β-phenethyloxy and phenylpropyloxy oranother C₇-C₉ aralkoxy group, acetoxy, propionyloxy, butyryloxy,isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy oranother C₂-C₇ acyloxy group, oxo, methylsulfonyloxy, ethylsulfonyloxy,propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy or anotherC₁-C₆ alkylsulfonyloxy group consisting of a straight or branched alkyland sulfonyloxy, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaroyl and hexanoyl or another C₂-C₇ acyl group, carboxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonylor another C₂-C₇ alkoxycarbonyl group consisting of a straight orbranched alkyl and oxycarbonyl group, carbamoyl, N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl,N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl,N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl,N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyland N,N-dipropylcarbamoyl or another C₂-C₇ alkylcarbamoyl groupconsisting of a straight or branched alkyl, cycloalkyl and carbamoylgroup, amino, methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino,hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino, cyclopropylmethylamino, dimethylamino,N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, N-methylbutyl-amino, N-methyl-t-butylamino,N-ethylisopropylamino, dipropylamino, diisopropylamino andethylbutylamino or another C₁-C₆ alkylamino group consisting of astraight or branched alkyl, cycloalkyl and amino group, acetylamino,propionylamino, butyrylamino, isobutyrylamino, valerylamino andhexanoylamino or another C₂-C₇ acylamino group, methoxycarbonylamino,ethoxycarbonylamino and t-butoxycarbonylamino or another C₂-C₈alkoxycarbonylamino group, methylsulfonylamino, ethylsulfonylamino,butylsulfonylamino and t-butylsulfonylamino or another C₁-C₆alkylsulfonylamino group, a cyano group, a nitro group, methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,s-butylthio, t-butylthio, pentylthio and hexylthio or another C₁-C₆alkylthio group, methylsulfynyl, ethylsulfynyl, propylsulfynyl,isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl, s-butylsulfynyl,t-butylsulfynyl, pentylsulfynyl and cyclopentylsulfynyl or another C₁-C₆alkylsulfynyl group consisting of a straight or branched alkyl,cycloalkyl and sulfynyl group, methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butyl-sulfonyl, isobutylsulfonyl,s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl,cyclopentylsulfonyl and cyclohexylsulfonyl or another C₁-C₆alkylsulfonyl group consisting of a straight or branched alkyl,cycloalkyl and sulfonyl group, a sulfo group, a sulfamoyl group,methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl,isopropylaminosulfonyl, butylaminosulfonyl, isobutylamino-sulfonyl,s-butylaminosulfonyl, pentylaminosulfonyl, dimethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl,dipropylaminosulfonyl, cyclopropyl-aminosulfonyl,cyclopentylaminosulfonyl, cyclohexylamino-sulfonyl andcyclopropylmethylaminosulfonyl or another C₁-C₆ aminosulfonyl groupconsisting of a straight or branched alkyl, a cycloalkyl andaminosulfonyl group, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexylor another alicyclic hydrocarbon group having 3 to 6 carbon atoms,methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl,isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl,s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl,4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl oranother aliphatic hydrocarbon group having 1 to 6 carbon atoms which maycontain a straight or branched unsaturated bond.

As the substituent of the substituted alicyclic hydrocarbon group having3 to 10 carbon atoms as G¹, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, aC₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylaminogroup, an alicyclic hydrocarbon group having 3 to 6 carbon atoms or analiphatic hydrocarbon group having 1 to 6 carbon atoms, may further besubstituted with (one or more substituents selected from the groupconsisting of a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a C₂-C₇ acyl group such as methoxymethyloxygroup, 2-methoxyethoxy group, formyl group, trifluoroacetyl group,acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbambyl, N-cyclopropylcarbamoyl orN-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methyl-propylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a C₁-C₇ acylamino group such astrifluoroacetylamino group, formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; and a cyano group).

In the formula (I), when G¹ represents a substituted or unsubstituteddivalent aromatic hydrocarbon group having 6 to 14 carbon atoms,examples of the aromatic hydrocarbon group having 6 to 14 carbon atomsinclude a compound having at least one aromatic ring on its molecule,such as benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene,fluorene, phenanthrene or anthracene.

Examples of such preferred aromatic hydrocarbon group having 6 to 14carbon atoms of G¹ include benzene, naphthalene and indane. Examples ofmore preferred aromatic hydrocarbon group having 6 to 14 carbon atoms ofG¹ include benzene.

Exemplary substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms of G¹ include a fluorine atom, a chlorineatom, a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇-acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxygroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group, an amino group, an optionally substitutedC₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group,a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, acyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, aC₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 3 to 6 carbon atoms and an optionallysubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Specific examples of the substituent of the substituted aromatichydrocarbon group having 6 to 14 carbon atoms of G¹ include the same asthose specifically exemplified as the substituents of the substitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹.

As the substituent of the substituted aromatic hydrocarbon group having6 to 14 carbon atoms, the C₁-C₇ alkoxy group, the C₂-C₇ acyl group, theC₂-C₇ alkylcarbamoyl group, the C₁-C₆ alkylamino group, the C₂-C₇acylamino group, the alicyclic hydrocarbon group having 3 to 6 carbonatoms or the aliphatic hydrocarbon group having 1 to 6 carbon atoms, mayfurther be substituted with (one or more substituents selected from thegroup consisting of a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; and a cyano group).

Preferred examples of the substituents of the substituted aromatichydrocarbon group having 6 to 14 carbon atoms of G₁ include a fluorineatom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy group consistingof a straight or branched alkyl and oxy group, including methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a cyanogroup; a nitro group; a carboxyl group; a hydroxy group; an amino group;a C₁-C₆ mono or dialkylamino group consisting of a straight or branchedalkyl and amino group, including methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino,pentylamino, hexylamino, dimethylamino, N-ethylmethylamino,diethylamino, N-methylpropylamino, N-methylisopropylamino,N-methylbutyl-amino, N-methyl-t-butylamino, N-ethylisopropylamino,dipropylamino, diisopropylamino and ethylbutylamino; a carbamoyl group;an aminosulfonyl group; an alicyclic hydrocarbon group having 3 to 6carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; a C₂-C₇ acyl group including acetyl, propionyl, butyryl,isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group includingmethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; aC₁-C₆ alkylsulfonyl group including methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl; aC₂-C₇ alkoxycarbonyl group including acetoxy, propionyloxy, butyryloxy,isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; aC₂-C₇ acylamino group including acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino and hexanoylamino;trifluoromethyl group, trifluoromethoxy group, and an aliphatichydrocarbon group having 1 to 6 carbon atoms which may contain astraight or branched unsaturated bond, including methyl, ethyl, vinyl,ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl,1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl,2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl,isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl,2-methylpentyl and 1-ethylbutyl.

Specifically, examples of more preferred substituents of the substitutedaromatic hydrocarbon group having 6 to 14 carbon atoms include afluorine atom, a chlorine atom, a bromine atom, C₁-C₆ alkoxy group,cyano group, a nitro group, a carboxyl group, a hydroxy group, an aminogroup, a C₁-C₆ mono or dialkylamino group, a carbamoyl group, analicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acylgroup, a C₁-C₆ alkylsulfonyl group, a C₂-C₇ alkoxycarboxyl group,trifluoromethyl group, trifluoromethoxy group, and a C₁-C₆ alkyl groupincluding methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl,2-methylpentyl and 1-ethylbutyl. Examples of particularly preferredsubstituents include a fluorine atom, a chlorine atom, a C₁-C₆ alkoxygroup, a cyano group, a nitro group, a carboxyl group, a hydroxy group,an amino group, a C₁-C₆ mono or dialkylamino group, an alicyclichydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, atrifluoromethyl group, a trifluoromethoxy group and a C₁-C₆ alkyl group.

In the formula (I), when G¹ represents a divalent group derived fromheterocyclic compounds having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on itssubstituted or unsubstituted ring, examples of such heterocycliccompounds include monocyclic, bicyclic or tricyclic heterocycliccompounds, such as furan, thiophene, pyrrole, pyrroline, pyrrolidine,oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole,thiazolidine, isothiazole, isothiazolidine, furazan, imidazole,imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine,triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran,thiopyran, tetrahydrothiopyran, tetrahydrofuran, 1,3-dioxolane,1,4-dioxane, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran,dibenzofuran, 1,4-dioxacycloheptane, benzothiophene, indole,1,2-methylene-dioxybenzene, benzimidazole, benzothiazole, benzooxazole,chroman, isochroman, quinoline, decahydrbquinoline, isoquinoline,phthalazine, cinnoline, 1,8-naphthylidine,1,2,3,4-tetrahydroisoquinoline, quinazoline, quinoxaline, purine,pteridine, azetidine, morpholine, thiomorpholine, piperidine,homopiperidine, piperazine, homopiperazine, indoline, isoindoline,phenoxazine, phenazine, phenothiazine, pyrrolopyrimidine,pyrazolpyrimidine or quinuclidine.

Preferred examples of the heterocyclic compound having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring of G¹ include monocyclic or bicyclicC₂-C₉ aromatic heterocyclic compounds having 1 to 3 atoms selected fromthe group consisting of an oxygen atom, a nitrogen atom and a sulfuratom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole,thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine,pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran,1,2-methylenedioxybenzene, benzimidazole, indole, quinoline,isoquinoline, quinazoline, phthalazine, cinnoline or 1,8-naphthylidin;or monocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine,thiomorpholine, homopiperidine, homopiperazine,1,2,3,6-tetrahydropyridine or piperazine.

The heterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering of G¹ links to A² on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group linking to A² on acarbon atom include divalent groups derived from monocyclic or bicyclicC₃-C₉ aromatic heterocyclic compounds having 1 or 2 atoms selected fromthe group consisting of an oxygen atom, a nitrogen atom and a sulfuratom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole,thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine;pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran,1,2-methylenedioxybenzene, benzimidazole, indole, quinoline,isoquinoline or quinazoline.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring, the heterocyclic group linking toA² on a nitrogen atom, include divalent groups derived from monocyclicor bicyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine,thiomorpholine, homopiperidine, homopiperazine,1,2,3,6-tetrahydropyridine or piperazine. More preferred examples of themonocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, in the ring, include piperidine, homopiperidine,morpholine, homopiperazine and piperazine.

Exemplary substituent of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of G¹, include a fluorineatom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group,an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, aC₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, acarboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, anoptionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, anoptionally substituted C₁-C₆ alkylamino group, an optionally substitutedC₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonylgroup, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfogroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, and an optionally substituted aliphatic hydrocarbongroup having 1 to 6 carbon atoms.

Specific examples of the substituent of the heterocyclic group having 1to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on its substituted ring of G¹ includethe same as those exemplified in the substituted alicyclic hydrocarbongroup having 3 to 10 carbon atoms of G¹.

As the substituent of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of G¹, a C₁-C₇ alkoxy group, aC₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylaminogroup, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3to 6 carbon atoms and aliphatic hydrocarbon group having 1 to 6 carbonatoms may further be substituted with (one or more substituents selectedfrom the group consisting of a fluorine atom; a chlorine atom; a bromineatom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl orisovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl ort-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group suchas N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl,N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; and a cyano group).

Preferred examples of the substituent of the heterocyclic group having 1to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on its substituted ring of G¹, include afluorine atom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy groupconsisting of a straight or branched alkyl and oxy group, includingmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy andhexyloxy; a cyano group; a nitro group; a carboxyl group; a hydroxygroup; an amino group; a C₁-C₆ mono or dialkylamino group consisting ofa straight or branched alkyl and amino group, including methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino,N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino,N-ethylisopropylamino, dipropylamino, diisopropylamino andethylbutylamino; a carbamoyl group; an aminosulfonyl group; an alicyclichydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; a C₂-C₇ acyl group includingacetyl, propionyl butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆alkylthio group including methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio,pentylthio and hexylthio; a C₁-C₆ alkylsulfonyl group, includingmethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl,pentylsulfonyl and hexylsulfonyl; a C₂-C₇ alkoxycarbonyl group includingacetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy and hexanoyloxy; a C₂-C₇ acylamino groupincluding acetylamino, propionylamino, butyrylamino, isobutyrylamino,valerylamino and hexanoylamino; trifluoromethyl, trifluoromethoxy, andan aliphatic hydrocarbon group having 1 to 6 carbon atoms which maycontain a straight or branched unsaturated bond, including methyl,ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl,isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl,4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl.

Specifically, more preferred examples of the substituent of theheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on itssubstituted ring of G¹, include a fluorine atom, a chlorine atom, abromine atom, C₁-C₆ alkoxy group, cyano group, a nitro group, a carboxylgroup, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylaminogroup, a carbamoyl group, an alicyclic hydrocarbon group having 3 to 6carbon atoms, a C₂-C₇ acyl group, a C₁-C₆ alkylsulfonyl group, a C₂-C₇alkoxycarboxyl group, a trifluoromethyl group, a trifluoromethoxy group,and a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl,butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl,t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl. Examples ofparticularly preferred substituents include a fluorine atom, a chlorineatom, a C₁-C₆ alkoxy group, a cyano group, a nitro group, a carboxylgroup, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylaminogroup, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, aC₂-C₇ acyl group, a trifluoromethyl group, a trifluoromethoxy group anda C₁-C₆ alkyl group.

In the present invention, G¹ in the formula (I) is preferably a singlebond, a monocyclic aliphatic hydrocarbon group having 3 to 6 carbonatoms, a phenylene group, a monocyclic or bicyclic aromatic hydrocarbongroup having 3 to 9 carbon atoms having 1 or 2 atoms selected from amonga group consisting of an oxygen atom, a nitrogen atom, and a sulfuratom, in the ring, or a monocyclic heterocyclic group having 2 to 9carbon atoms having 1 or 2 atoms selected from among a group consistingof an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In the formula (I), G² represents a hydrogen atom, a substituted orunsubstituted acyclic aliphatic hydrocarbon group having 1 to 10 carbonatoms, a substituted or unsubstituted alicyclic hydrocarbon group having3 to 10 carbon atoms, a substituted or unsubstituted aromatichydrocarbon group having 6 to 14 carbon atoms, or a substituted orunsubstituted heterocyclic group having 1 to 4 atoms selected from amonga group consisting of an oxygen atom, a nitrogen atom, and a sulfuratom, in the ring.

In formula (I), when G² represents a substituted or unsubstitutedacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms,examples of such a acyclic aliphatic hydrocarbon group having 1 to 10carbon atoms of G² include an alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl,neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl,hexyl, heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl,6-methylheptyl, octyl, nonyl or decyl, an alkenyl group such as vinyl,1-methylvinyl, 1-ethylvinyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 2-methyl-1-butenyl,1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,5-hexadienyl, 2-heptenyl,2-octenyl, 2-nonenyl or 2-decenyl, or an alkynyl group such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl,3,3-dimethyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl,1-methyl-3-hexynyl, 2-heptynyl, 2-octynyl, 2-nonynyl or 2-decynyl.

Specifically, more preferred examples of such aliphatic hydrocarbongroup having 1 to 10 carbon atoms include a straight or branched C₁-C₆alkyl group which may contain a unsaturated bond such as methyl, ethyl,propyl, isopropyl, butyl, pentyl, hexyl, vinyl, 1-prophenyl, 1-butenyl,ethynyl or 1-propynyl. Particularly preferred examples of such a acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms include astraight or branched C₁-C₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl or hexyl.

Exemplary substituents of the substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms of G² include: a fluorine atom; achlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₇alkoxy group consisting of a straight or branched alkyl group,cycloalkyl group and oxy group, including methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy,2-methylpentyloxy, 1-ethylbutoxy, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy,cyclopropylethyloxy, cyclopentyl methyloxy and cyclohexylmethyloxy; analkyldioxy group having 1 to 4 carbon atoms such as ethylene dioxy; aC₆-C₁₀ aryloxy group, including phenoxy, 1-naphthoxy and 2-naphthoxy; aC₇-C₉ aralkoxy group, including benzyloxy, α-phenethyloxy,β-phenethyloxy and phenylpropyloxy; a C₂-C₇ acyloxy group includingacetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy and hexanoyloxy; an oxo group; a C₁-C₆alkylsulfonyloxy group consisting of a straight or branched alkyl andsulfonyloxy, including oxo, methylsulfonyloxy, ethylsulfonyloxy,propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy; a C₂-C₇ acylgroup, including acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaroyl and hexanoyl; a carboxyl group; a C₂-C₇alkoxycarbonyl group consisting of a straight or branched alkyl andoxycarbonyl group, including methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,s-butoxycarbonyl and t-butoxycarbonyl; a carbamoyl group; a C₂-C₇alkylcarbamoyl group consisting of a straight or branched alkyl,cycloalkyl and carbamoyl group, including N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl,N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl,N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl,N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyland N,N-dipropylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupconsisting of a straight or branched alkyl, cycloalkyl and amino group,including methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino,hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino, cyclopropylmethylamino, dimethylamino,N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino,N-methylisopropylamino, dipropylamino, diisopropylamino andethylbutylamino; a C₂-C₇ acylamino group including acetylamino,propionylamino, butyrylamino, isobutyrylamino, valerylamino andhexanoylamino; a C₂-C₈ alkoxycarbonylamino group, includingmethoxycarbonylamino, ethoxycarbonylamino and t-butoxy-carbonylamino; aC₁-C₆ alkylsulfonylamino group including methylsulfonylamino,ethylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino; a cyanogroup; a nitro group; a C₁-C₆ alkylthio group including methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆alkylsulfynyl group consisting of a straight or branched alkyl,cycloalkyl and sulfynyl group, including methylsulfynyl, ethylsulfynyl,propylsulfynyl, isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl,s-butylsulfynyl, t-butylsulfynyl, pentylsulfynyl andcyclopentylsulfynyl; a C₁-C₆ alkylsulfonyl group consisting of astraight or branched alkyl, cycloalkyl and sulfonyl group, includingmethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl,pentylsulfonyl, hexylsulfonyl, cyclopentylsulfonyl andcyclohexylsulfonyl; a sulfo group; a sulfamoyl group; a C₁-C₆aminosulfonyl group consisting of a straight or branched alkyl,cycloalkyl and aminosulfonyl group, including methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl,butylaminosulfonyl, isobutyl-aminosulfonyl, s-butylaminosulfonyl,pentylaminosulfonyl, dimethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl,dipropylaminosulfonyl, cyclopropylaminosulfonyl,cyclopentylaminosulfonyl, cyclohexylaminosulfonyl andcyclopropylmethylaminosulfonyl; an alicyclic hydrocarbon group having 3to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; and an aliphatic hydrocarbon group having 1 to 6 carbonatoms which may contain a straight or branched unsaturated bond,including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl,isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl,s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl,4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl; anaromatic hydrocarbon group having 6 to 14 carbon atoms which is amonovalent group derived from monocyclic, bicyclic or tricyclic aromatichydrocarbon group, including benzene, naphthalene, indene, indane,1,2,3,4-tetrahydronaphthalene, and fluorene; and a monovalent groupderived from monocyclic, bicyclic or tricyclic heterocyclic compound,including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole,oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine,isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine,pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole,tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran,pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran,benzothiophene, indole, benzimidazole, benzothiazole, benzooxazole,chroman, isochroman, quinoline, decahydroquinoline, isoquinoline,quinazolin, quinoxaline, purine, pteridine, azetidine, morpholine,thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine,indoline, isoindoline, phenoxazine, phenazine, phenothiazine andquinuclidine, the heterocyclic compound (having 1 to 4 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, in the ring).

Preferred examples of the substituent of the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include afluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxygroup, an oxo group, an optionally substituted C₂-C₇ acyl group, acarboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, anoptionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, anoptionally substituted C₁-C₆ alkylamino group, an optionally substitutedC₂-C₇ acylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group,a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms andan optionally substituted heterocyclic group (having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring).

More preferred exemplary substituents of the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include afluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxygroup, a carboxyl group, an amino group, an optionally substituted C₁-C₆alkylamino group, a cyano group, a benzyl group, and an optionallysubstituted heterocyclic group (having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring).

As the substituent of the substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms as G², the heterocyclic group (having1 to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring), links to the aliphatichydrocarbon group having 1 to 10 carbon atoms as G² on a carbon atom ora nitrogen atom.

Preferred examples of the heterocyclic group (having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring), links to the aliphatic hydrocarbongroup having 1 to 10 carbon atoms as G² on a carbon atom, include amonovalent group derived from a monocyclic or bicyclic C₃-C₉ aromaticheterocyclic compound, including furan, pyrrole, thiophene, pyrazole,oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole,pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran,1,2-methylenedioxybenzene, benzimidazole, indole, quinoline,isoquinoline and quinazolin, the monovalent group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring.

Meanwhile, preferred examples of the heterocyclic group (having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring), links to the acyclic aliphatichydrocarbon group having 1 to 10 carbon atoms as G² on a nitrogen atom,include a monovalent group derived from a monocyclic C₂-C₉ heterocycliccompound, including pyrrolidine, piperidine, morpholine, thiomorpholine,homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine andpiperazine, the monovalent group having 1 or 2 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring.

As the substituent of the substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms as G², a C₁-C₇ alkoxy group, a C₂-C₇acyl group, C₂-C₇ alkylcarbamoyl, a C₁-C₆ alkylamino group, a C₂-C₇acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbonatoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms,aromatic hydrocarbon group having 6 to 14 carbon atoms, and heterocyclicgroup having 1 to 4 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring, may furtherbe substituted with (one or more substituents selected from the groupconsisting of: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropyl-carbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms, examples of thealicyclic hydrocarbon group having 3 to 10 carbon atoms of G² includecyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl group.Preferred examples of the alicyclic hydrocarbon group having 3 to 10carbon atoms of G² include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 3-cyclopentenyl, 4-cyclopentenyl, 1-cyclohexenyl,3-cyclohexenyl, 4-cyclohexenyl, and 1-cycloheptenyl.

Exemplary substituents of the substituted alicyclic hydrocarbon grouphaving 3 to 10 carbon atoms of G² include a fluorine atom, a chlorineatom, a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, C₁-C₄ alkylenedioxy group, a C₆-C₁₀aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxogroup, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoylgroup, an optionally substituted C₂-C₇ alkylcarbamoyl group, an aminogroup, an optionally substituted C₁-C₆ alkylamino group, an optionallysubstituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, aC₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonylgroup, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfogroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, and an optionally substituted aliphatic hydrocarbongroup having 1 to 6 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted alicyclichydrocarbon group having 3 to 10 carbon atoms of G² include the same asthose exemplified in the substituted aliphatic hydrocarbon group having1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having3 to 10 carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, aC₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylaminogroup, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, analiphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatichydrocarbon group having 6 to 14 carbon atoms, may further besubstituted with (one or more substituents selected from the groupconsisting of: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstitutedaromatic hydrocarbon group having 6 to 14 carbon atoms, examples of thearomatic hydrocarbon group having 6 to 14 carbon atoms include amonovalent group having at least one aromatic ring on its molecule, suchas benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene,fluorene, phenanthrene or anthracene. Examples of such preferredaromatic hydrocarbon group having 6 to 14 carbon atoms of G² include aphenyl group.

Exemplary substituents of the aromatic hydrocarbon group having 6 to 14carbon atoms of G² include at least one substituent selected from thegroup consisting of a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxygroup, a C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, acarboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, anoptionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, anoptionally substituted C₁-C₆ alkylamino group, an optionally substitutedC₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonylgroup, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfogroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, an optionally substituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms, and an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted C₆-C₁₄ aromatichydrocarbon group of G² include the same as those exemplified in thesubstituent of the substituted aliphatic hydrocarbon group having 1 to10 carbon atoms of G².

As the substituents of the aromatic hydrocarbon group having 6 to 14carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group,an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatichydrocarbon group having 1 to 6 carbon atoms, and an aromatichydrocarbon group having 6 to 14 carbon atoms, may further besubstituted with (one or more substituents selected from the groupconsisting of: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a heterocyclic group having 1 to4 atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on its substituted or unsubstituted ring,examples of such heterocyclic group include a monovalent group derivedfrom monocyclic, bicyclic or tricyclic compounds, including furan,thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine,isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole,isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole,pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole,pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine,pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran,benzothiophene, indole, 1,2-methylene-dioxybenzene, benzimidazole,benzothiazole, benzooxazole, chroman, isochroman, quinoline,decahydroquinoline, isoquinoline, quinazolin, quinoxaline, purine,pteridine, azetidine, morpholine, thiomorpholine, piperidine,homopiperidine, piperazine, homopiperazine, indoline, isoindoline,phenoxazine, phenazine, phenothiazine and quinuclidine.

Preferred examples of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring of G² include 2-pyridyl, 3-pyridyl,4-pyridyl, piperidino, 2-piperizyl, 3-piperizyl, 4-piperizyl,morpholino, 1-homopiperidinyl, 1-pyrrolidinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 4-isooxazolyl,2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 4-triazolyl, 5-tetrazolyl,1-piperazinyl, 4-tetrahydropyranyl, 2-1,3,4-oxadiazolyl,4-1,2,3-thiadiazolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-indolyl,3-indolyl, 5-benzoimidazolyl and 2-1,2,3,4-tetrahydroisoquinolinylgroup.

The heterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering of G², links to A⁴ on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring of G², the heterocyclic group linking toA⁴ on a carbon atom, include a monovalent group derived from amonocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 or2 atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene,pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole,imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene,benzofuran, 1,2-methylenedioxy-benzene, benzimidazole, indole,quinoline, isoquinoline or quinazolin.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring of G², the heterocyclic grouplinking to A⁴ on a nitrogen atom, include a monovalent group derivedfrom a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring, such as pyrrolidine, piperidine,morpholine, thiomorpholine, homopiperidine, homopiperazine,1,2,3,6-tetrahydropyridine or piperazine.

More preferred examples of the heterocyclic group as G² include amonovalent group derived from a monocyclic C₄-C₆ heterocyclic compoundhaving 1 or 2 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring, such aspiperidine, homopiperidine, morpholine, homopiperazine, or piperazine.

Exemplary substituents of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of G² include at least onesubstituent selected from the group consisting of a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a hydroxy group, anoptionally substituted C₁-C₇ alkoxy group, a C₁-C₄ alkylenedioxy group,a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group,an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substitutedC₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, acarbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group,an amino group, an optionally substituted C₁-C₆ alkylamino group, anoptionally substituted C₂-C₇ acylamino group, a C₂-C₈alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyanogroup, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynylgroup, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionallysubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, andan optionally substituted aromatic hydrocarbon group having 6 to 14carbon atoms and.

The substituents of the heterocyclic group having 1 to 4 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, in the ring of G² are as defined above for the substituentof the substituted aliphatic hydrocarbon group having 1 to 10 carbonatoms of G².

As the substituent of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of G², a C₁-C₇ alkoxy group, aC₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylaminogroup, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbonatoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms,may further be substituted with (one or more substituents selected fromthe group consisting of: a fluorine atom; a chlorine atom; a bromineatom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl orisovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl ort-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group suchas N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl,N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the present description, when G¹, G², or the substituent of G²represents a substituted or unsubstituted aromatic hydrocarbon group, asubstituted or unsubstituted alicyclic hydrocarbon group, or asubstituted or unsubstituted heterocyclic group, the aromatichydrocarbon group, alicyclic hydrocarbon group, or heterocyclic group ispreferably selected from the group consisting of cyclopropane,cyclopentane, cyclohexane, cyclohexene, cycloheptane, *nolvolnane,adamantine, benzene, naphthalene, indane, indoles, 1,3-benzodioxol,benzoimidazol, benzotriazol, pyrazol, imidazol, pyrazoron, thiazol,tetrazol, 1,2,4-oxadiazol, isooxazol, furan, thiophene, pyridine,pyradine, pyrrole, morpholine, benzofuran, benzothiophene, piperazine,pyrrolidine, homopiperizine, tetrahydroisoquinoline, pyrimidine, andquinazoline.

Next, an explanation will be given of preferred combinations of A¹, A²,G¹, A³, A⁴ and G² in the formula (I).

When both of A¹ and A³ represent aliphatic hydrocarbon group, at leastone of A² and G¹ is not a single bond.

The preferred combinations of A¹, A², G¹, A³, A⁴ and G², and preferredcombinations including also substituents of them if they havesubstituents are basically preferably combinations of those preferablyselected from among A¹, A², G¹, A³, A⁴ and G², and substituents of them.Then, more preferred combinations are combinations of more preferredelements.

In the formula (I), A¹ represents a divalent acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms, particularly preferablyrepresents —(CH₂)₂— or —(CH₂)₃—.

More preferably, A² simultaneously represents those other than thesingle bond, and especially preferably A² represents —C(═O)—, —C(═O)—O—,—C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—,—NH—C(═O)—NMe-, or —NH—C(═S)—. Specifically preferably A² represents—C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

Meanwhile, where A¹ represents a single bond, preferably also Arepresents a single bond.

Preferred combinations of G¹, A³, A⁴ and G² of G¹-G² portion includecombinations of 1 to 10 of the following table.

Combi- nation G¹ A³ A⁴ G² 1 Group other Single bond Single bond Hydrogenthan single atom bond 2 Single bond Group other than Single bondHydrogen single bond atom 3 Group other Single bond Single bond Groupother than single than a bond hydrogen atom 4 Single bond Group otherthan Single bond Group other single bond than a hydrogen atom 5 Groupother Single bond Group other Group other than single than single than abond bond hydrogen atom 6 Single bond Group other than Group other Groupother single bond than single than a bond hydrogen atom 7 Group otherGroup other than Single bond Group other than single single bond than abond hydrogen atom 8 Group other Group other than Group other Groupother than single single bond than single than a bond bond hydrogen atom9 Group other Group other than Group other Hydrogen than single singlebond than single atom bond bond 10 Single bond Single bond Single bondHydrogen atom

In the table, in combinations of numbers 4 to 7, A³ represents analkylene group having 1 to 3 carbon atoms.

Also, in the combination of number 5, A⁴ preferably represents —C(═O)—,—C(═O)—NH—, —O—, or —NH—C(═O)—.

Also, in the combination of number 8, A⁴ preferably represents —O—.

Further, combinations of the following a) to f) are preferable.

-   a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or    —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a    divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon    atoms.-   b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—,    —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other    than the single bond.-   c) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents a single bond, and G¹ represents an optionally    substituted heterocyclic group (note, where a heterocyclic group of    G¹ is 5 or 6 membered monocyclic ring, the 5 or 6 membered    monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion    represents those other than the hydrogen atom).-   d) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, and G¹ represents an    optionally substituted aromatic hydrocarbon group, an optionally    substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms,    or an optionally substituted heterocyclic group (note, where the    aromatic hydrocarbon group of G¹ is a phenyl group, or where the    heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the    phenyl group or 5 or 6 membered monocyclic heterocyclic group of G¹    is substituted, or A³-G² portion represents those other than the    hydrogen atom).-   e) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, G¹ and A⁴ represent the    single bond, A³ represents an optionally substituted acyclic    aliphatic hydrocarbon group having 1 to 10 carbon atoms, G²    represents an optionally substituted alicyclic hydrocarbon group    having 5 to 10 carbon atoms, an optionally substituted aromatic    hydrocarbon group, or optionally substituted heterocyclic group.-   f) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, G¹ represents the single    bond, A³ represents an optionally substituted acyclic aliphatic    hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents    —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(═O)—,    —NR¹²⁵—C(═O)—, —NR¹²⁶—S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—,    —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—,    —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—,—C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—,—NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents—C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In the formula (I), A⁵ represents a single bond or represents a groupthat links R² with a carbon atom of a pyrrole ring to which A⁵ isbonded, in the form of R²—NR²⁰¹-pyrrole ring (R²⁰¹ represents a hydrogenatom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbonatoms), when A⁵ bonds R² and a carbon atom of a pyrrole ring to which A⁵is bonded, in the form of R²—NR²⁰¹-pyrrole ring, examples of the acyclicaliphatic hydrocarbon group having 1 to 4 carbon atoms of R²⁰¹ are thesame as those exemplified as R¹⁰¹ of A² described above. Preferredexamples of R¹⁰² include a hydrogen atom, methyl, ethyl or propyl group,and specifically preferably hydrogen atom and methyl group.

Preferred examples of A⁵ include a single bond, —NH—, and N(CH₃)—, andspecifically preferably single bond.

In the formula (I), R² represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, an iodine atom, an optionally substitutedacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, anoptionally substituted alicyclic hydrocarbon group having 3 to 8 carbonatoms, an optionally substituted aromatic hydrocarbon group having 6 to14 carbon atoms, or an optionally substituted heterocyclic group having1 to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring.

R² in the formula (I) is preferably a chlorine atom or a bromine atomamong a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom.

In the formula (I), when R² represents an optionally substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms, examples ofacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R²are the same as those exemplified of the acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms of G². Preferred examples of theacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R²include methyl, ethyl, isopropyl, butyl, isobutyl, t-butyl, t-pentyl,vinyl, 2-propenyl, 2-methyl-1-propenyl, and 2-propenyl.

Substituents for the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of R² include at least one substituentselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxygroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group, an amino group, an optionally substitutedC₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group,a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, acyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, aC₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 1 to 6 carbon atoms, an optionallysubstituted acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms, an optionally substituted aromatic hydrocarbon group having 6 to14 carbon atoms, and an optionally substituted heterocyclic group(having 1 to 4 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms of R² includethe same as those exemplified as the substituents of the substitutedacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms as R², a C₁-C₇ alkoxy group, a C₂-C₇ acylgroup, C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, aC₂-C₇-acylamino group, an alicyclic hydrocarbon group having 3 to 6carbon atoms, a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms, aromatic hydrocarbon group having 6 to 14 carbon atoms, andheterocyclic group (having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering), may further be substituted with (one or more substituentsselected from the group consisting of: a fluorine atom; a chlorine atom;a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxygroup; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group;a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl,valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonylor t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl groupsuch as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R² represents a substituted or unsubstitutedalicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of thealicyclic hydrocarbon group having 3 to 8 carbon atoms of R² the same asdefined above for the substituents of the substituted alicyclichydrocarbon group having 3 to 8 carbon atoms of G². Preferred examplesof the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R²include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Among them,the cyclopropyl group is preferred.

Exemplary substituents of the substituted alicyclic hydrocarbon grouphaving 3 to 8 carbon atoms of R² include at least one substituentselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxygroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group, an amino group, an optionally substitutedC₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group,a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, acyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, aC₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionallysubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, anoptionally substituted aromatic hydrocarbon group having 6 to 14 carbonatoms, and an optionally substituted heterocyclic group (having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclichydrocarbon group having 3 to 8 carbon atoms of R² include the same asthose exemplified in the substituted alicyclic hydrocarbon group having1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having3 to 8 carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, aC₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylaminogroup, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, analiphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatichydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group(having 1 to 4 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring), may further besubstituted with (one or more substituents selected from the groupconsisting of: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropyl-carbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino,N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² is a substituted or unsubstituted aromatichydrocarbon group having 6 to 14 carbon atoms, examples of the aromatichydrocarbon group having 6 to 14 carbon atoms of R² include the same asthose exemplified in the aromatic hydrocarbon group having 6 to 14carbon atoms of G². Examples of such preferred aromatic hydrocarbongroup having 6 to 14 carbon atoms of R² include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms include at least one substituent selectedfrom the group consisting of a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, a hydroxy group, a C₁-C₆ alkyl group, anoptionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, aC₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, acarboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, anoptionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, anoptionally substituted C₁-C₆ alkylamino group, an optionally substitutedC₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonylgroup, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfogroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, an optionally substituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, and an optionallysubstituted heterocyclic group (having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring).

Specific examples of the substituent of the substituted aromatichydrocarbon group having 6 to 14 carbon atoms R² include the same asthose exemplified for the substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms of G².

As the substituent of the aromatic hydrocarbon group having 6 to 14carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group,an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatichydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbongroup having 6 to 14 carbon atoms and heterocyclic group (having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring), may further be substituted with(one or more substituents selected from the group consisting of: afluorine atom; a chlorine atom; a bromine atom; an iodine atom; ahydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy orcyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; aformyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such asacetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² represents a heterocyclic group having 1 to4 atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on its substituted or unsubstituted ring of R²,examples of heterocyclic group of R² include the same as thoseexemplified for the heterocyclic group of G². The heterocyclic group ofR² links to A⁵ on a carbon atom or a nitrogen atom.

Examples of preferred heterocyclic group linking to A⁵ on a carbon atominclude a monocyclic or cyclic C₃-C₉ aromatic heterocyclic group having1 to 3 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring, such as furyl, thienyl,pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl,indolyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl,benzoimidazolyl or benzooxazolyl. More preferred example of theheterocyclic group include a monocyclic or bicyclic C₃-C₉ aromaticheterocyclic compound having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 2-furyl, 2-thienyl, 2-pyrrolyl, 2-imidazolyl,5-imidazolyl, 4-pyrazolyl, 2-oxazolyl, 5-oxazolyl, 5-isooxazolyl,2-thiazolyl, 5-thiazolyl, 5-isothiazolyl, 3-isothiazolyl, 2-pyridyl,2-pyrimidinyl, 2-benzofuranyl or 2-benzothiophenyl group. Further,particularly preferable examples of the heterocyclic group include amonocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring, and most preferably, 2-furyl, 2-thienyl,2-pyrrolyl, 2-pyridyl or 4-pyrazolyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring, links to A⁵ on a nitrogen atom,include 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl, piperidino,morpholino, 1-homopiperidinyl and 1-piperazinyl. When the heterocyclicgroup having 1 to 4 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom on a ring of R², links toA⁵ on a nitrogen atom, A⁵ represents a single bond.

Exemplary substituents of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the substituted ring of R² include at least onesubstituent selected from the group consisting of a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a hydroxy group, anoptionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, aC₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, acarboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, anoptionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, anoptionally substituted C₁-C₆ alkylamino group, an optionally substitutedC₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonylgroup, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfogroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, an optionally substituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, and an optionallysubstituted heterocyclic group (having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring).

Specific examples of the substituent of the heterocyclic group having 1to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on its substituted ring of R² includethe same as those exemplified as the substituents of the substitutedaliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of R², a C₁-C₇ alkoxy group, aC₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylaminogroup, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3to 6 carbon atoms, aliphatic hydrocarbon group having 1 to 6 carbonatoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and aheterocyclic group (having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering) may further be substituted with (one or more substituents selectedfrom the group consisting of: a fluorine atom; a chlorine atom; abromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl orisovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl ort-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group suchas N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isbbutyrylamino or valerylamino; aC₁-C₆-alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

Among exemplary substituents of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on its substituted ring of R², preferred examplesof the substituent include a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, a hydroxy group, a cyano group, a nitro group, anamino group, a C₁-C₆ mono or dialkylamino group consisting of a straightor branched alkyl group and an amino group, such as substituted orunsubstituted methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino,hexylamino, dimethylamino, N-ethylmethylamino, diethylamino,N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino,N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino,diisopropylamino and ethylbutylamino, a carboxyl group, an optionallysubstituted saturated a C₁-C₆ alkyl group including a substituted orunsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl,isohexyl, 2-methylpentyl and 1-ethylbutyl, an alicyclic hydrocarbongroup having 3 to 6 carbon atoms including cyclopropyl, cyclobutyl,cyclo pentyl and cyclohexyl, an optionally substituted C₁-C₆ alkoxygroup consisting of a straight or branched alkyl group and an oxy group,including a substituted or unsubstituted methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy, a C₂-C₇ acylgroup, including a substituted or unsubstituted acetyl, propionyl,butyryl, isobutyryl, pivaroyl and hexanoyl, a C₁-C₆ alkylthio group,including methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio,trifluoromethyl group, trifluoromethoxy group, a C₂-C₇ acylamino group,including substituted or unsubstituted acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino and hexanoylamino, and aC₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkylgroup and a carbamoyl group, including a substituted or unsubstitutedN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl,N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl andN,N-diethylcarbamoyl.

More preferred examples of the substituent of the heterocyclic grouphaving 1 to 4 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom on its substituted ring as R²,include one or more of a fluorine atom, a chlorine atom, a bromine atom,an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxylgroup, an alkoxycarbonyl group, a substituted or unsubstituted C₁-C₆alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆alkoxy group.

Here, an explanation will be given of preferred combinations of R² andA⁵ of the formula (I).

In combinations of R² and A⁵ of the formula (I) in the presentinvention, when R² is a fluorine atom, a chlorine atom, a bromine atom,or an iodine atom, A⁵ represents a single bond.

Preferred examples of the combinations of R² and A⁵ of the formula (I)in the present invention include those representing an aliphatichydrocarbon group having 1 to 10 carbon atoms wherein A⁵ represents asingle bond, and R² may be substituted, an optionally substitutedalicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, oran optionally substituted heterocyclic group. Specific preferredcombinations are combinations representing an aliphatic hydrocarbongroup having 1 to 10 carbon atoms wherein A⁵ represents a single bond,and R² may be substituted, an optionally substituted alicyclichydrocarbon group having 3 to 8 carbon atoms, an optionally substitutedphenyl group, or an optionally substituted heterocyclic group having 1or 2 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring. Among them, cases where R²represents a cyclopropyl group, a cyclobutyl group, a cyclopropylmethylgroup, a methyl group, an ethyl group, a vinyl group, an isopropylgroup, an isobutyl group or 2-methyl-1-propenyl group are preferred.

Also, combinations of A⁵ and R² in which A⁵ represents a single bond andR² represents a thienyl group, a pyridyl group, a furyl group, apyrazolyl group or a phenyl group are preferable, wherein the thienylgroup, the pyridyl group, the furyl group, the pyrazolyl group or thephenyl group may be further substituted by one or more of a C₁-C₄ alkylgroup, a C₁-C₄ alkoxy group, a C₂-C₄ acyl group, a hydroxy group, acarboxyl group, an alkoxycarbonyl group, a fluorine atom or a chlorineatom.

Also a combination wherein A⁵ is NR²⁰¹—, and R² represents a hydrogenatom or an optionally substituted aliphatic hydrocarbon group having 1to 10 carbon atoms is preferred.

In the formula (I), A⁶ is a single bond, a group that links a carbonatom of a pyrrole ring in which R³ and A⁶ are linked to each other inthe form of R³—NR³⁰¹-pyrrole ring, R³—C(═O)-pyrrole ring,R³—NR³⁰²—C(═O)-pyrrole ring, R³—NR³⁰³—C(═S)-pyrrole ring,R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring, R³—C(═O)—NR³⁰⁶-pyrrole ring,R³—NR³⁰⁷—CH═N-pyrrole ring, R³—O—C(═O)-pyrrole ring, R³—C(═O)—O-pyrrolering, R³—O-pyrrole ring, R³—S-pyrrole ring, R³—S(═O)-pyrrole ring,R³—S(═O)₂-pyrrole ring, R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, R³—C≡C-pyrrolering, or R³—S(═O)₂—C≡C-pyrrole ring (R³⁰¹ through R³⁰⁹ are eachindependently a hydrogen atom or a C₁-C₄ aliphatic hydrocarbon group.)

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—NR³⁰¹-pyrrole ring, examples of such C₁-C₄ aliphatichydrocarbon group of R³⁰¹ include the same as those selected as theexamples of R¹⁰¹ in A². Examples of such preferred R³⁰¹ include ahydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom ispreferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—NR³⁰²—C(═O)-pyrrole ring, examples of such C₁-C₄aliphatic hydrocarbon group of R³⁰² include the same as those selectedas the examples of R¹ in A². Examples of such preferred R³⁰² include ahydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom ispreferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—NR³⁰³—C(═S)-pyrrole ring, examples of such C₁-C₄aliphatic hydrocarbon group of R³⁰³ include the same as those selectedas the examples of R¹⁰¹ in A². Examples of such preferred R³⁰³ include ahydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom ispreferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—NR³⁰⁴——C(═O)—NR³⁰⁵-pyrrole ring, examples of suchC₁-C₄ aliphatic hydrocarbon group of R³⁰⁴ and R³⁰⁵ include the same asthose selected as the examples of R¹⁰¹ in A². Examples of such preferredR³⁰⁴ and R³⁰⁵ include a hydrogen atom, methyl, and ethyl group.Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—C(═O)—NR³⁰⁶-pyrrole ring, examples of such C₁-C₄aliphatic hydrocarbon group of R³⁰⁶ include the same as those selectedas the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁶ include ahydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom ispreferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—NR³⁰⁷—CH═N-pyrrole ring, examples of such C₁-C₄aliphatic hydrocarbon group of R³⁰⁷ include the same as those selectedas the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁷ include ahydrogen atom, methyl, and ethyl group. Particularly, methyl group ispreferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each otherin the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, examples of such C₁-C₄aliphatic hydrocarbon group of R³⁰⁸ and R³⁰⁸ include the same as thoseselected as the examples of R¹⁰¹ in A².

In the formula (I), R³ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a nitro group, asubstituted or unsubstituted saturated aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms, a substituted or unsubstituted alicyclichydrocarbon group having 3 to 8 carbon atoms, a substituted orunsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, ora heterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom.

As R³ in the formula (I), among a fluorine atom, a chlorine atom, abromine atom, and an iodine atom, a chlorine atom, a bromine atom, andan iodine atom are preferred.

In the formula (I), when R³ represents a substituted or unsubstitutedacyclic saturated aliphatic hydrocarbon group having 1 to 10 carbonatoms, examples of the acyclic saturated aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of R³ include an alkyl group, includingmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,pentyl, isopentyl, neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl,1-ethylbutyl, hexyl, heptyl, 2-methylhexyl, 5-methylhexyl,1,1-dimethylpentyl, 6-methylheptyl, octyl, nonyl, and decyl. Preferredexamples of the acyclic saturated aliphatic hydrocarbon group having 1to 10 carbon atoms of R³ include methyl, ethyl, isopropyl, butyl,t-butyl, and t-pentyl group.

As the substituent of the substituted acyclic saturated aliphatichydrocarbon group having 1 to 10 carbon atoms of R³ include at least onesubstituent selected from the group consisting of a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a hydroxy group, anoptionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, aC₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, an optionallysubstituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonylgroup, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoylgroup, an amino group, an optionally substituted C₁-C₆ alkylamino group,an optionally substituted C₂-C₇ acylamino group, a C₂-C₈alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyanogroup, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynylgroup, an optionally substituted alicyclic hydrocarbon group having 3 to6 carbon atoms, an optionally substituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms and an optionallysubstituted heterocyclic group (having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring).

Specific examples of the substituent of the substituted acyclicsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³include the same as those exemplified in the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted acyclic saturated aliphatichydrocarbon group having 1 to 10 carbon atoms of R³, a C₁-C₇ alkoxygroup, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbongroup having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbonatoms and a heterocyclic group (having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring), may further be substituted with (one or more substituentsselected from the group consisting of: a fluorine atom; a chlorine atom;a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxygroup; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group;a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl,valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonylor t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl groupsuch as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino,N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstitutedalicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of thealicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include thesame as those exemplified in the alicyclic hydrocarbon group having 3 to10 carbon atoms of G². Preferred examples of the alicyclic hydrocarbongroup having 3 to 8 carbon atoms of R² include cyclopropyl, cyclobutyland cyclopentyl, cyclohexyl.

Exemplary substituents of the substituted alicyclic hydrocarbon grouphaving 3 to 8 carbon atoms of R³ include at least one substituentselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇ acyloxy group, an optionally substituted C₂-C₇ acylgroup, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoylgroup, an optionally substituted C₂-C₇ alkylcarbamoyl group, an aminogroup, an optionally substituted C₁-C₆ alkylamino group, an optionallysubstituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, acyano group, a nitro group, an optionally substituted alicyclichydrocarbon group having 3 to 6 carbon atoms, an optionally substitutedaliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms andan optionally substituted heterocyclic group (having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclichydrocarbon group having 3 to 8 carbon atoms of R³ include the same asthose exemplified as the substituents of the substituted thesubstituents of the substituted aliphatic hydrocarbon group having 1 to10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having3 to 8 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, aC₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino,an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatichydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbongroup having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to4 atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring), may further be substituted with(one or more substituents selected from the group consisting of: afluorine atom; a chlorine atom; a bromine atom; an iodine atom; ahydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy orcyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; aformyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such asacetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropylcarbamoyl orN-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ Cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstitutedaromatic hydrocarbon group having 6 to 14 carbon atoms, examples of thearomatic hydrocarbon group having 6 to 14 carbon atoms of R³ include thesame as those exemplified in the aromatic hydrocarbon group having 6 to14 carbon atoms of G². Preferred examples of the aromatic hydrocarbongroup having 6 to 14 carbon atoms of R³ include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms of R³ include at least one substituentselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxygroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group, an amino group, an optionally substitutedC₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group,a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, acyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, aC₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionallysubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, anoptionally substituted aromatic hydrocarbon group having 6 to 14 carbonatoms and an optionally substituted heterocyclic group (having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted aromatichydrocarbon group having 6 to 14 carbon atoms of R³ include the same asthose exemplified in the substituent of the substituted aliphatichydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted aromatic hydrocarbon group having6 to 14 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, aC₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylaminogroup, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, analiphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatichydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group(having 1 to 4 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring), may further besubstituted with (one or more substituents selected from the groupconsisting of: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxygroup; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group suchas acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxogroup; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoylgroup; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-cyclopropyl-carbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino,N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a heterocyclic group having 1 to4 atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on its substituted or unsubstituted ring,examples of such heterocyclic group having 1 to 4 atoms selected fromthe group consisting of an oxygen atom, a nitrogen atom and a sulfuratom on the ring of R³ include the same as those exemplified in theheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thering of G².

The heterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thering of R³ links to A⁶ on a carbon atom or a nitrogen atom.

Preferred examples of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the ring of R³ and linking to A⁶ on a carbon atom,include a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic grouphaving 1 to 3 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring, including furyl,thienyl, pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, benzofuranyl, indolyl, benzothienyl, quinolyl, isoquinolyl,quinazolyl, benzoimidazolyl and benzooxazolyl, preferably 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2-oxazolyl, 2-thiazolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-N-oxopyridyl, 3-N-oxopyridyl,4-N-oxopyridyl, 3-pyrazolyl, 4-pyrazolyl, 4-imidazolyl, 2-pyrimidinyl,or 5-pyrimidinyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on the ring of R³ and linking to A⁶ on a nitrogenatom, include 1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-pyrrolidinyl,piperidino, morpholino, 1-homopiperidinyl and 1-piperazinyl, preferably1-imidazolyl.

When the heterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thering of R³ links to A⁶ on a nitrogen atom, A⁶ is a single bond, or agroup that links a carbon atom of a pyrrole ring in which R³ and A⁶ arelinked to each other in the form of R³—C(═O)-pyrrole ring.

Exemplary substituents of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the ring of R³ include at least one substituentselected from the group consisting of a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a hydroxy group, an optionallysubstituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxygroup, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxygroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group, an amino group, an optionally substitutedC₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group,a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, acyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, aC₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substitutedalicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionallysubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, anoptionally substituted aromatic hydrocarbon group having 6 to 14 carbonatoms and an optionally substituted heterocyclic group (having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom, in the ring).

Specific examples of the substituent of the heterocyclic group having 1to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on its substituted ring of R³ includethe same as those exemplified in the substituted aliphatic hydrocarbongroup having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on its substituted ring of R³, a C₁-C₇ alkoxy group, aC₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylaminogroup, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3to 6 carbon atoms and an aliphatic hydrocarbon group having 1 to 6carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms,and a heterocyclic group (having 1 to 4 atoms selected from the groupconsisting of oxygen atom, a nitrogen atom and a sulfur atom in thering) may further be substituted with (one or more substituents selectedfrom the group consisting of: a fluorine atom; a chlorine atom; abromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl orisovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl ort-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group suchas N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl orN-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino,N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; aC₄-C₆ cyclic amino group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇acylamino group such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino or valerylamino; aC₁-C₆-alkylsulfonylamino group such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitrogroup; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; atrifluoromethyl group; and a trifluoromethoxy group).

Among those exemplified as substituents of the heterocyclic group having1 to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom on the ring of R³, preferred examplesthereof include: a fluorine atom; a chlorine atom; a bromine atom; aniodine atom; a hydroxy group; a cyano group; a nitro group; an aminogroup; a C₁-C₆ mono or dialkylamino group consisting of a straight orbranched alkyl group and an amino group, including a substituted orunsubstituted methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino,hexylamino, dimethylamino, N-ethylmethylamino, diethylamino,N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino,N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino,diisopropylamino and ethylbutylamino; a carboxyl group; a saturated aC₁-C₆ alkyl group including a substituted or unsubstituted methyl,ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and1-ethylbutyl; an alicyclic hydrocarbon group having 3 to 6 carbon atomsincluding cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₁-C₆alkoxy group consisting of a straight or branched alkyl group and an oxygroup, including a substituted or unsubstituted methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a C₂-C₇ acyl groupincluding a substituted or unsubstituted acetyl, propionyl, butyryl,isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group, includingmethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; atrifluoromethyl group; a trifluoromethoxy group; a C₂-C₇ acylamino groupincluding a substituted or unsubstituted acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; and aC₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkylgroup and a carbamoyl group including a substituted or unsubstitutedN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl,N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl andN,N-diethylcarbamoyl.

More preferred substituents of the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on the ring of R³, include a fluorine atom, achlorine atom, a bromine atom, a substituted or unsubstituted C₁-C₆alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆alkoxy group. Specifically, a methyl group and an ethyl group arepreferred.

In the formula (I), A⁶ is a group that links R³ and a carbon atom of apyrrole ring in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring orR³—C≡C-pyrrole ring. R³ represents a trimethylsilyl group, a formylgroup, an optionally substituted C₂-C₇ acyl group, a carboxyl group, aC₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substitutedC₂-C₇ alkylcarbamoyl group or a cyano group, preferred examples thereofinclude a formyl group, an acetyl group, a carboxyl group, amethoxycarbonyl group, an ethoxycarbonyl group and a cyano group.

Here, an explanation will be given of preferred combinations of R³ andA⁶ in the formula (I).

As combinations of R³ and A⁶ of the formula (I) in the presentinvention, when R³ represents a fluorine atom, a chlorine atom, abromine atom, or an iodine atom, A³ represents a single bond.

Also, when R³ represents a trimethylsilyl group, a formyl group, anoptionally substituted a C₂-C₇ acyl group, a carboxyl group, a C₂-C₇alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇alkylcarbamoyl group, or a cyano group, A is a group that links a carbonatom of a pyrrole ring in which R³ and A⁶ are linked to each other inthe form of a carbon atom of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring orR³—C≡C-pyrrole carbon atom.

Preferred combinations of R³ and A⁶ of the formula (I) in the presentinvention include cases where A⁶ represents a single bond and R³represents an optionally substituted aromatic hydrocarbon group having 6to 14 carbon atoms or an optionally substituted heterocyclic group.Among them, a case where R³ represents a thienyl group, a furyl group, apyrrolyl group, a pyrazolyl group or a phenyl group optionallysubstituted with one or more alkyl group having 1 to 4 carbon atoms ispreferred.

Also a case where A⁶ represents a single bond, and R³ represents apyridyl group or 1-oxypyridyl group or pyrazolyl group orN-methylpyrazolyl group optionally substituted by an alkyl group having1 to 4 carbon atoms or one halogen atom.

In addition, the following combinations can be mentioned: a combinationin which A⁶ represents a single bond, and R³ is a fluorine atom,chlorine atom, bromine atom, or iodine atom, a combination in which A⁶represents a single bond, and R³ is a substituted or unsubstitutedsaturated acyclic saturated aliphatic hydrocarbon group having 1 to 10carbon atoms; a combination in which A⁶ represents a single bond, and R³is a substituted or unsubstituted alicyclic hydrocarbon group having 3to 8 carbon atoms; a combination in which A⁶ represents a single bond,and R³ is a substituted or unsubstituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms; a combination in which A⁶ represents asingle bond, and R³ is a substituted or unsubstituted monocyclic C₃-C₅aromatic heterocyclic group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering; a combination in which A⁶ is a group that links R³ and a carbonatom of a pyrrole ring in which A⁶ is linked in the form of the carbonatom of a R³—NH—C(═O)-pyrrole ring, and R³ is a hydrogen atom; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstitutedacyclic saturated aliphatic hydrocarbon group having 1 to 10 carbonatoms; a combination in which A⁶ is a group that links R³ and a carbonatom of a pyrrole ring in which A⁶ is linked in the form of the carbonatom of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is asubstituted or unsubstituted alicyclic hydrocarbon group having 3 to 8carbon atoms; a combination in which A⁶ is a group that links R³ and acarbon atom of a pyrrole ring in which A⁶ is linked in the form of thecarbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted orunsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of theR³—C(═O)—NH-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromaticheterocyclic group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thesubstituted or unsubstituted ring; a combination in which A⁶ is a groupthat links R³ and a carbon atom of a pyrrole ring in which A⁶ is linkedin the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is ahydrogen atom; a combination in which A⁶ is a group that links R³ and acarbon atom of a pyrrole ring in which A⁶ is linked in the form of thecarbon atom of a R³—NH-pyrrole ring, and R³ is a substituted orunsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to10 carbon atoms; a combination in which A⁶ is a group that links R³ anda carbon atom of a pyrrole ring in which A⁶ is linked in the form of thecarbon atom of a R³—NH-pyrrole ring, and R³ is a substituted orunsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—NH-pyrrole ring, and R³ is a substituted or unsubstituted aromatichydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶is linked in the form of the carbon atom of R³—NH-pyrrole ring, and R³is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the substituted or unsubstituted ring; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—HC═CH-pyrrole ring, and R³ is a hydrogen atom; a combination in whichA⁶ is a group that links R³ and a carbon atom of a pyrrole ring in whichA⁶ is linked to each other in the form of the carbon atom of aR³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted acyclicsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; acombination in which A⁶ is a group that links a carbon atom of a pyrrolering in which R³ and A⁶ are linked to each other in the form of thecarbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted orunsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted aromatichydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, andR³ is a monocyclic C₃-C₅-aromatic heterocyclic group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the substituted or unsubstituted ring; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—C≡C-pyrrole ring, and R³ is a hydrogen atom; a combination in whichA⁶ is a group that links R³ and a carbon atom of a pyrrole ring in whichA⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring,and R³ is a substituted or unsubstituted acyclic saturated aliphatichydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, andR³ is a substituted or unsubstituted alicyclic hydrocarbon group having3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³and a carbon atom of a pyrrole ring in which A⁶ is linked in the form ofthe carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted orunsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; acombination in which A⁶ is a group that links R³ and a carbon atom of apyrrole ring in which A⁶ is linked in the form of the carbon atom of aR³—C≡C-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclicgroup having 1 or 2 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom on the substituted orunsubstituted ring; and a combination in which A⁶ is a group that linksR³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the formof the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a trimethylsilylgroup or cyano group.

Here, an explanation will be given of preferred combinations of R²-A⁵portion and R³-A⁶ portion in the formula (I).

Preferred combinations of R²-A⁵ portion and R³-A⁶ portion include caseswhere both of A⁵ and A⁶ represent a single bond. In this case, morepreferred combinations include cases where R² represents a cyclopropylgroup, a cyclobutyl group, a cyclopropylmethyl group, a methyl group, anethyl group, a vinyl group, an isopropyl group, an isobutyl group or2-methyl-1-propenyl group, and R³ represents a pyridyl group or1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl groupoptionally substituted with one alkyl group having 1 to 4 carbon atomsor one halogen atom.

Also combinations wherein both of A⁵ and A⁶ represent a single bond, andR² represents a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₂-C₄ acylgroup, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, athienyl group, a pyridyl group, a furyl group, a pyrrolyl group, apyrazolyl group or phenyl group which may be substituted by one or moreof a fluorine atom or a chlorine atom, and R³ represents a pyridyl groupor 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl groupwhich may be substituted by one alkyl group having 1 to 4 carbon atomsor one halogen atom can be mentioned as preferred examples.

Further, an explanation will be given of preferred combinations of A¹-G²portion, R²-A⁵ portion and R³-A⁶ portion in the formula (I). Basically,preferably those mentioned as preferred examples for A¹-G² portion,R²-A⁵ portion and R³-A⁶ portion are combined, and more preferably morepreferred examples are combined.

More specifically, in the combinations of the following a) to f)mentioned as preferred combinations of the A¹-G² portion, further a casewhere both of A⁵ and A⁶ represent a single bond is preferred.

-   a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or    —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a    divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon    atoms.-   b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—,    —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other    than the single bond.-   c) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents a single bond, and G¹ represents an optionally    substituted heterocyclic group (note, where a heterocyclic group of    G¹ is 5 or 6 membered monocyclic ring, 5 or 6 membered monocyclic    heterocyclic group of G¹ is substituted, or A³-G² portion represents    those other than a hydrogen atom).-   d) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, and G¹ represents an    optionally substituted aromatic hydrocarbon group, an optionally    substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms,    or an optionally substituted heterocyclic group (note, where the    aromatic hydrocarbon group of G¹ is a phenyl group, or where the    heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the    phenyl group of G¹ or 5 or 6 membered monocyclic heterocyclic group    is substituted, or A³-G² portion represents those other than a    hydrogen atom).-   e) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, G¹ and A⁴ represent the    single bond, A³ represents an optionally substituted acyclic    aliphatic hydrocarbon group having 1 to 10 carbon atoms, G²    represents an optionally substituted alicyclic hydrocarbon group    having 5 to 10 carbon atoms, an optionally substituted aromatic    hydrocarbon group, or optionally substituted heterocyclic group.-   f) A¹ represents a divalent acyclic aliphatic hydrocarbon group    having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A²    represents those other than a single bond, G¹ represents the single    bond, A³ represents an optionally substituted acyclic aliphatic    hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents    —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(═O)—,    —NR¹²⁵—C(═O)—, —NR¹²⁶ —S(═O)₂—, —NR¹²⁷—C(═O)—O—,    —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—,    —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—,—C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—,—NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents—C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In these cases of combinations, further preferably R² represents anoptionally substituted acyclic aliphatic hydrocarbon group having 1 to10 carbon atoms, an optionally substituted alicyclic hydrocarbon grouphaving 3 to 8 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms or an optionallysubstituted heterocyclic group, and R³ represents an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms or anoptionally substituted heterocyclic group.

In further detail, in these cases, combinations wherein R² represents analiphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclichydrocarbon group having 3 to 8 carbon atoms, an optionally substitutedphenyl group, or an optionally substituted heterocyclic group having 1or 2 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring, and R³ represents athienyl group, a pyridyl group, a furyl group, a pyrrolyl group, apyrazolyl group or a phenyl group optionally substituted with one ormore alkyl group having 1 to 4 carbon atoms are specifically preferred.Especially, preferred combinations can include cases where R² representsa cyclopropyl group, a methyl group, an ethyl group, a vinyl group, anisopropyl group, an isobutyl group or 2-methyl-1-propenyl group, and R³represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group orN-methylpyrazolyl group which may be substituted by an alkyl grouphaving 1 to 4 carbon atoms or one halogen atom, and cases where R²represents a thienyl group, a pyridyl group, a furyl group, a pyrrolylgroup, a pyrazolyl group or phenyl group which may be substituted by oneor more of a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, and a chlorinegroup, and R³ represents a pyridyl group or 1-oxypyridyl group orpyrazolyl group or N-methylpyrazolyl group which may be substituted byan alkyl group having 1 to 4 carbon atoms or one halogen atom.

In the pyrrolo-pyrimidinone derivatives of the formula (I), specificpreferred combinations of -G¹-A³-A⁴-G² portion include groupsrepresented by the following formulae, K001-K431. In the respectivechemical formula, symbol “- - -” is used to denote a binding sitebetween A² and the group -G¹-A³-A⁴-G².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specificexamples of preferred combinations of the -A⁵-R² portion, groupsrepresented by the following formulae, J001-J166 may be mentioned. Inthe respective chemical formulae, symbol “- - -” indicates a bindingsite between a carbon atom of a pyrrole ring and -A⁵-R².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specificexamples of preferred combinations of the -A⁶-R³ portion, groupsrepresented by the following formulae, T001-T181 may be mentioned. Inthe respective chemical formulae, symbol “- - -” indicates a bindingsite between a carbon atom of a pyrrole ring and -A⁶-R³.

Specific examples of the pyrrolo-pyrimidinone derivatives of formula (I)include the compounds having groups described in the following Table 1as A¹, the compounds having groups described in the following Table 1 asA², the compounds having groups represented by K001-K431 indicated inthe formula as -G¹-A³-A⁴-G², the compounds having groups represented byJ01-J166 indicated in the formula as -A⁵-R², the compounds having groupsrepresented by T001-T181 indicated in the formula as -A⁶-R³, and thecompounds consisting of any combination of groups mentioned above withregard to each moiety. Preferable examples among such compounds arelisted in Tables below.

TABLE 1 Compound no. -A¹- -A²- -G¹-A³-A⁴-G² -A⁵-R² -A⁶-R³ 1 —(CH₂)₂——C(═O)— K002 J001 T148 2 —(CH₂)₂— —C(═O)— K002 J001 T151 3 —(CH₂)₂——C(═O)— K003 J001 T148 4 —(CH₂)₂— —C(═O)— K003 J001 T151 5 —(CH₂)₂——C(═O)— K004 J001 T148 6 —(CH₂)₂— —C(═O)— K004 J001 T151 7 —(CH₂)₂——C(═O)— K005 J001 T148 8 —(CH₂)₂— —C(═O)— K005 J001 T151 9 —(CH₂)₂——C(═O)— K007 J001 T148 10 —(CH₂)₂— —C(═O)— K007 J001 T152 11 —(CH₂)₂——C(═O)— K008 J001 T148 12 —(CH₂)₂— —C(═O)— K008 J001 T152 13 —(CH₂)₂——C(═O)— K009 J001 T148 14 —(CH₂)₂— —C(═O)— K009 J001 T152 15 —(CH₂)₂——C(═O)— K012 J001 T148 16 —(CH₂)₂— —C(═O)— K012 J001 T152 17 —(CH₂)₂——C(═O)— K107 J001 T148 18 —(CH₂)₂— —C(═O)— K107 J001 T168 19 —(CH₂)₂——C(═O)— K108 J001 T148 20 —(CH₂)₂— —C(═O)— K108 J001 T169 21 —(CH₂)₂——C(═O)— K112 J001 T148 22 —(CH₂)₂— —C(═O)— K112 J001 T170 23 —(CH₂)₂——C(═O)— K129 J001 T148 24 —(CH₂)₂— —C(═O)— K129 J001 T171 25 —(CH₂)₂——C(═O)— K133 J001 T148 26 —(CH₂)₂— —C(═O)— K133 J001 T172 27 —(CH₂)₂——C(═O)— K137 J001 T148 28 —(CH₂)₂— —C(═O)— K137 J001 T173 29 —(CH₂)₂——C(═O)—NH— K007 J001 T148 30 —(CH₂)₂— —C(═O)—NH— K012 J001 T148 31—(CH₂)₂— —C(═O)—O— K001 J001 T148 32 —(CH₂)₂— —C(═O)—O— K002 J001 T15133 —(CH₂)₂— —C(═O)—O— K193 J001 T152 34 —(CH₂)₂— —C(═O)—O— K227 J001T169 35 —(CH₂)₂— —C(═O)—O— K002 J001 T148 36 —(CH₂)₂— —NH— K181 J012T148 37 —(CH₂)₂— —NH— K181 J012 T151 38 —(CH₂)₂— —NH— K181 J012 T152 39—(CH₂)₂— —NH— K181 J012 T169 40 —(CH₂)₂— —NH— K181 J045 T148 41 —(CH₂)₂——NH— K181 J045 T151 42 —(CH₂)₂— —NH— K181 J045 T152 43 —(CH₂)₂— —NH—K181 J045 T169 44 —(CH₂)₂— —NH— K181 J045 T170 45 —(CH₂)₂— —NH— K181J045 T172 46 —(CH₂)₂— —NH— K182 J012 T148 47 —(CH₂)₂— —NH— K182 J012T151 48 —(CH₂)₂— —NH— K182 J012 T152 49 —(CH₂)₂— —NH— K182 J012 T169 50—(CH₂)₂— —NH— K182 J045 T148 51 —(CH₂)₂— —NH— K182 J045 T151 52 —(CH₂)₂——NH— K182 J045 T152 53 —(CH₂)₂— —NH— K182 J045 T169 54 —(CH₂)₂— —NH—K182 J045 T170 55 —(CH₂)₂— —NH— K182 J045 T172 56 —(CH₂)₂— —NH— K183J012 T148 57 —(CH₂)₂— —NH— K183 J012 T151 58 —(CH₂)₂— —NH— K183 J012T152 59 —(CH₂)₂— —NH— K183 J012 T169 60 —(CH₂)₂— —NH— K183 J045 T148 61—(CH₂)₂— —NH— K183 J045 T151 62 —(CH₂)₂— —NH— K183 J045 T152 63 —(CH₂)₂——NH— K183 J045 T169 64 —(CH₂)₂— —NH— K183 J045 T170 65 —(CH₂)₂— —NH—K183 J045 T172 66 —(CH₂)₂— —NH— K184 J012 T148 67 —(CH₂)₂— —NH— K184J012 T151 68 —(CH₂)₂— —NH— K184 J012 T152 69 —(CH₂)₂— —NH— K184 J012T169 70 —(CH₂)₂— —NH— K184 J045 T148 71 —(CH₂)₂— —NH— K184 J045 T151 72—(CH₂)₂— —NH— K184 J045 T152 73 —(CH₂)₂— —NH— K184 J045 T169 74 —(CH₂)₂——NH— K184 J045 T170 75 —(CH₂)₂— —NH— K184 J045 T172 76 —(CH₂)₂— —NH—K185 J012 T148 77 —(CH₂)₂— —NH— K185 J012 T151 78 —(CH₂)₂— —NH— K185J012 T152 79 —(CH₂)₂— —NH— K185 J012 T169 80 —(CH₂)₂— —NH— K185 J045T004 81 —(CH₂)₂— —NH— K185 J045 T005 82 —(CH₂)₂— —NH— K185 J045 T090 83—(CH₂)₂— —NH— K185 J045 T129 84 —(CH₂)₂— —NH— K185 J045 T148 85 —(CH₂)₂——NH— K185 J045 T151 86 —(CH₂)₂— —NH— K185 J045 T152 87 —(CH₂)₂— —NH—K185 J045 T169 88 —(CH₂)₂— —NH— K185 J045 T170 89 —(CH₂)₂— —NH— K185J045 T172 90 —(CH₂)₂— —NH— K186 J012 T148 91 —(CH₂)₂— —NH— K186 J012T151 92 —(CH₂)₂— —NH— K186 J012 T152 93 —(CH₂)₂— —NH— K186 J012 T169 94—(CH₂)₂— —NH— K186 J045 T148 95 —(CH₂)₂— —NH— K186 J045 T151 96 —(CH₂)₂——NH— K186 J045 T152 97 —(CH₂)₂— —NH— K186 J045 T169 98 —(CH₂)₂— —NH—K186 J045 T170 99 —(CH₂)₂— —NH— K186 J045 T172 100 —(CH₂)₂— —NH— K187J012 T148 101 —(CH₂)₂— —NH— K187 J012 T151 102 —(CH₂)₂— —NH— K187 J012T152 103 —(CH₂)₂— —NH— K187 J012 T169 104 —(CH₂)₂— —NH— K187 J045 T148105 —(CH₂)₂— —NH— K187 J045 T151 106 —(CH₂)₂— —NH— K187 J045 T152 107—(CH₂)₂— —NH— K187 J045 T169 108 —(CH₂)₂— —NH— K187 J045 T170 109—(CH₂)₂— —NH— K187 J045 T172 110 —(CH₂)₂— —NH— K188 J012 T148 111—(CH₂)₂— —NH— K188 J012 T151 112 —(CH₂)₂— —NH— K188 J012 T152 113—(CH₂)₂— —NH— K188 J012 T169 114 —(CH₂)₂— —NH— K188 J045 T148 115—(CH₂)₂— —NH— K188 J045 T151 116 —(CH₂)₂— —NH— K188 J045 T152 117—(CH₂)₂— —NH— K188 J045 T169 118 —(CH₂)₂— —NH— K188 J045 T170 119—(CH₂)₂— —NH— K188 J045 T172 120 —(CH₂)₂— —NH— K189 J012 T148 121—(CH₂)₂— —NH— K189 J012 T151 122 —(CH₂)₂— —NH— K189 J012 T152 123—(CH₂)₂— —NH— K189 J012 T169 124 —(CH₂)₂— —NH— K189 J045 T148 125—(CH₂)₂— —NH— K189 J045 T151 126 —(CH₂)₂— —NH— K189 J045 T152 127—(CH₂)₂— —NH— K189 J045 T169 128 —(CH₂)₂— —NH— K189 J045 T170 129—(CH₂)₂— —NH— K189 J045 T172 130 —(CH₂)₂— —NH— K190 J012 T148 131—(CH₂)₂— —NH— K190 J012 T151 132 —(CH₂)₂— —NH— K190 J012 T152 133—(CH₂)₂— —NH— K190 J012 T169 134 —(CH₂)₂— —NH— K190 J045 T148 135—(CH₂)₂— —NH— K190 J045 T151 136 —(CH₂)₂— —NH— K190 J045 T152 137—(CH₂)₂— —NH— K190 J045 T169 138 —(CH₂)₂— —NH— K190 J045 T170 139—(CH₂)₂— —NH— K190 J045 T172 140 —(CH₂)₂— —NH— K191 J012 T148 141—(CH₂)₂— —NH— K191 J012 T151 142 —(CH₂)₂— —NH— K191 J012 T152 143—(CH₂)₂— —NH— K191 J012 T169 144 —(CH₂)₂— —NH— K191 J045 T148 145—(CH₂)₂— —NH— K191 J045 T151 146 —(CH₂)₂— —NH— K191 J045 T152 147—(CH₂)₂— —NH— K191 J045 T169 148 —(CH₂)₂— —NH— K191 J045 T170 149—(CH₂)₂— —NH— K191 J045 T172 150 —(CH₂)₂— —NH— K192 J012 T148 151—(CH₂)₂— —NH— K192 J012 T151 152 —(CH₂)₂— —NH— K192 J012 T152 153—(CH₂)₂— —NH— K192 J012 T169 154 —(CH₂)₂— —NH— K192 J045 T148 155—(CH₂)₂— —NH— K192 J045 T151 156 —(CH₂)₂— —NH— K192 J045 T152 157—(CH₂)₂— —NH— K192 J045 T169 158 —(CH₂)₂— —NH— K192 J045 T170 159—(CH₂)₂— —NH— K192 J045 T172 160 —(CH₂)₂— —NH— K193 J012 T148 161—(CH₂)₂— —NH— K193 J012 T151 162 —(CH₂)₂— —NH— K193 J012 T152 163—(CH₂)₂— —NH— K193 J012 T169 164 —(CH₂)₂— —NH— K193 J045 T148 165—(CH₂)₂— —NH— K193 J045 T151 166 —(CH₂)₂— —NH— K193 J045 T152 167—(CH₂)₂— —NH— K193 J045 T169 168 —(CH₂)₂— —NH— K193 J045 T170 169—(CH₂)₂— —NH— K193 J045 T172 170 —(CH₂)₂— —NH— K194 J012 T148 171—(CH₂)₂— —NH— K194 J012 T151 172 —(CH₂)₂— —NH— K194 J012 T152 173—(CH₂)₂— —NH— K194 J012 T169 174 —(CH₂)₂— —NH— K194 J045 T148 175—(CH₂)₂— —NH— K194 J045 T151 176 —(CH₂)₂— —NH— K194 J045 T152 177—(CH₂)₂— —NH— K194 J045 T169 178 —(CH₂)₂— —NH— K194 J045 T170 179—(CH₂)₂— —NH— K194 J045 T172 180 —(CH₂)₂— —NH— K195 J012 T148 181—(CH₂)₂— —NH— K195 J012 T151 182 —(CH₂)₂— —NH— K195 J012 T152 183—(CH₂)₂— —NH— K195 J012 T169 184 —(CH₂)₂— —NH— K195 J045 T148 185—(CH₂)₂— —NH— K195 J045 T151 186 —(CH₂)₂— —NH— K195 J045 T152 187—(CH₂)₂— —NH— K195 J045 T169 188 —(CH₂)₂— —NH— K195 J045 T170 189—(CH₂)₂— —NH— K195 J045 T172 190 —(CH₂)₂— —NH— K196 J012 T148 191—(CH₂)₂— —NH— K196 J012 T151 192 —(CH₂)₂— —NH— K196 J012 T152 193—(CH₂)₂— —NH— K196 J012 T169 194 —(CH₂)₂— —NH— K196 J045 T148 195—(CH₂)₂— —NH— K196 J045 T151 196 —(CH₂)₂— —NH— K196 J045 T152 197—(CH₂)₂— —NH— K196 J045 T169 198 —(CH₂)₂— —NH— K196 J045 T170 199—(CH₂)₂— —NH— K196 J045 T172 200 —(CH₂)₂— —NH— K197 J012 T148 201—(CH₂)₂— —NH— K197 J012 T151 202 —(CH₂)₂— —NH— K197 J012 T152 203—(CH₂)₂— —NH— K197 J012 T169 204 —(CH₂)₂— —NH— K197 J045 T003 205—(CH₂)₂— —NH— K197 J045 T004 206 —(CH₂)₂— —NH— K197 J045 T005 207—(CH₂)₂— —NH— K197 J045 T077 208 —(CH₂)₂— —NH— K197 J045 T090 209—(CH₂)₂— —NH— K197 J045 T148 210 —(CH₂)₂— —NH— K197 J045 T151 211—(CH₂)₂— —NH— K197 J045 T152 212 —(CH₂)₂— —NH— K197 J045 T161 213—(CH₂)₂— —NH— K197 J045 T169 214 —(CH₂)₂— —NH— K197 J045 T170 215—(CH₂)₂— —NH— K197 J045 T172 216 —(CH₂)₂— —NH—C(═O)— K001 J001 T129 217—(CH₂)₂— —NH—C(═O)— K001 J045 T148 218 —(CH₂)₂— —NH—C(═O)— K002 J002T130 219 —(CH₂)₂— —NH—C(═O)— K002 J045 T148 220 —(CH₂)₂— —NH—C(═O)— K003J001 T148 221 —(CH₂)₂— —NH—C(═O)— K003 J001 T169 222 —(CH₂)₂— —NH—C(═O)—K003 J008 T134 223 —(CH₂)₂— —NH—C(═O)— K003 J008 T148 224 —(CH₂)₂——NH—C(═O)— K003 J009 T148 225 —(CH₂)₂— —NH—C(═O)— K003 J012 T148 226—(CH₂)₂— —NH—C(═O)— K003 J018 T148 227 —(CH₂)₂— —NH—C(═O)— K003 J018T152 228 —(CH₂)₂— —NH—C(═O)— K003 J035 T148 229 —(CH₂)₂— —NH—C(═O)— K003J035 T151 230 —(CH₂)₂— —NH—C(═O)— K003 J045 T148 231 —(CH₂)₂— —NH—C(═O)—K003 J052 T148 232 —(CH₂)₂— —NH—C(═O)— K003 J052 T169 233 —(CH₂)₂——NH—C(═O)— K003 J069 T148 234 —(CH₂)₂— —NH—C(═O)— K003 J069 T152 235—(CH₂)₂— —NH—C(═O)— K004 J003 T148 236 —(CH₂)₂— —NH—C(═O)— K004 J003T152 237 —(CH₂)₂— —NH—C(═O)— K004 J008 T148 238 —(CH₂)₂— —NH—C(═O)— K004J009 T135 239 —(CH₂)₂— —NH—C(═O)— K004 J009 T148 240 —(CH₂)₂— —NH—C(═O)—K004 J012 T148 241 —(CH₂)₂— —NH—C(═O)— K004 J020 T148 242 —(CH₂)₂——NH—C(═O)— K004 J020 T151 243 —(CH₂)₂— —NH—C(═O)— K004 J037 T148 244—(CH₂)₂— —NH—C(═O)— K004 J037 T169 245 —(CH₂)₂— —NH—C(═O)— K004 J045T148 246 —(CH₂)₂— —NH—C(═O)— K004 J054 T148 247 —(CH₂)₂— —NH—C(═O)— K004J054 T152 248 —(CH₂)₂— —NH—C(═O)— K004 J071 T148 249 —(CH₂)₂— —NH—C(═O)—K004 J071 T151 250 —(CH₂)₂— —NH—C(═O)— K005 J008 T148 251 —(CH₂)₂——NH—C(═O)— K005 J009 T148 252 —(CH₂)₂— —NH—C(═O)— K005 J012 T145 253—(CH₂)₂— —NH—C(═O)— K005 J012 T148 254 —(CH₂)₂— —NH—C(═O)— K005 J045T148 255 —(CH₂)₂— —NH—C(═O)— K006 J008 T148 256 —(CH₂)₂— —NH—C(═O)— K006J009 T148 257 —(CH₂)₂— —NH—C(═O)— K006 J012 T148 258 —(CH₂)₂— —NH—C(═O)—K006 J014 T148 259 —(CH₂)₂— —NH—C(═O)— K007 J004 T148 260 —(CH₂)₂——NH—C(═O)— K007 J004 T169 261 —(CH₂)₂— —NH—C(═O)— K007 J008 T148 262—(CH₂)₂— —NH—C(═O)— K007 J009 T148 263 —(CH₂)₂— —NH—C(═O)— K007 J012T148 264 —(CH₂)₂— —NH—C(═O)— K007 J015 T149 265 —(CH₂)₂— —NH—C(═O)— K007J021 T148 266 —(CH₂)₂— —NH—C(═O)— K007 J021 T152 267 —(CH₂)₂— —NH—C(═O)—K007 J038 T148 268 —(CH₂)₂— —NH—C(═O)— K007 J038 T151 269 —(CH₂)₂——NH—C(═O)— K007 J045 T148 270 —(CH₂)₂— —NH—C(═O)— K007 J055 T148 271—(CH₂)₂— —NH—C(═O)— K007 J055 T169 272 —(CH₂)₂— —NH—C(═O)— K007 J072T148 273 —(CH₂)₂— —NH—C(═O)— K007 J072 T152 274 —(CH₂)₂— —NH—C(═O)— K008J005 T148 275 —(CH₂)₂— —NH—C(═O)— K008 J005 T151 276 —(CH₂)₂— —NH—C(═O)—K008 J008 T148 277 —(CH₂)₂— —NH—C(═O)— K008 J008 T152 278 —(CH₂)₂——NH—C(═O)— K008 J009 T148 279 —(CH₂)₂— —NH—C(═O)— K008 J009 T152 280—(CH₂)₂— —NH—C(═O)— K008 J012 T148 281 —(CH₂)₂— —NH—C(═O)— K008 J012T152 282 —(CH₂)₂— —NH—C(═O)— K008 J018 T151 283 —(CH₂)₂— —NH—C(═O)— K008J022 T148 284 —(CH₂)₂— —NH—C(═O)— K008 J022 T169 285 —(CH₂)₂— —NH—C(═O)—K008 J039 T148 286 —(CH₂)₂— —NH—C(═O)— K008 J039 T152 287 —(CH₂)₂——NH—C(═O)— K008 J045 T148 288 —(CH₂)₂— —NH—C(═O)— K008 J045 T152 289—(CH₂)₂— —NH—C(═O)— K008 J056 T148 290 —(CH₂)₂— —NH—C(═O)— K008 J056T151 291 —(CH₂)₂— —NH—C(═O)— K008 J073 T148 292 —(CH₂)₂— —NH—C(═O)— K008J073 T169 293 —(CH₂)₂— —NH—C(═O)— K009 J006 T148 294 —(CH₂)₂— —NH—C(═O)—K009 J006 T152 295 —(CH₂)₂— —NH—C(═O)— K009 J008 T148 296 —(CH₂)₂——NH—C(═O)— K009 J009 T148 297 —(CH₂)₂— —NH—C(═O)— K009 J012 T148 298—(CH₂)₂— —NH—C(═O)— K009 J023 T148 299 —(CH₂)₂— —NH—C(═O)— K009 J023T151 300 —(CH₂)₂— —NH—C(═O)— K009 J040 T148 301 —(CH₂)₂— —NH—C(═O)— K009J040 T169 302 —(CH₂)₂— —NH—C(═O)— K009 J043 T152 303 —(CH₂)₂— —NH—C(═O)—K009 J045 T148 304 —(CH₂)₂— —NH—C(═O)— K009 J057 T148 305 —(CH₂)₂——NH—C(═O)— K009 J057 T152 306 —(CH₂)₂— —NH—C(═O)— K009 J074 T148 307—(CH₂)₂— —NH—C(═O)— K009 J074 T151 308 —(CH₂)₂— —NH—C(═O)— K010 J045T157 309 —(CH₂)₂— —NH—C(═O)— K011 J007 T148 310 —(CH₂)₂— —NH—C(═O)— K011J007 T169 311 —(CH₂)₂— —NH—C(═O)— K011 J008 T148 312 —(CH₂)₂— —NH—C(═O)—K011 J009 T148 313 —(CH₂)₂— —NH—C(═O)— K011 J012 T148 314 —(CH₂)₂——NH—C(═O)— K011 J024 T148 315 —(CH₂)₂— —NH—C(═O)— K011 J024 T152 316—(CH₂)₂— —NH—C(═O)— K011 J041 T148 317 —(CH₂)₂— —NH—C(═O)— K011 J041T151 318 —(CH₂)₂— —NH—C(═O)— K011 J045 T003 319 —(CH₂)₂— —NH—C(═O)— K011J045 T004 320 —(CH₂)₂— —NH—C(═O)— K011 J045 T005 321 —(CH₂)₂— —NH—C(═O)—K011 J045 T148 322 —(CH₂)₂— —NH—C(═O)— K011 J058 T148 323 —(CH₂)₂——NH—C(═O)— K011 J058 T169 324 —(CH₂)₂— —NH—C(═O)— K011 J063 T158 325—(CH₂)₂— —NH—C(═O)— K011 J075 T148 326 —(CH₂)₂— —NH—C(═O)— K011 J075T152 327 —(CH₂)₂— —NH—C(═O)— K012 J008 T148 328 —(CH₂)₂— —NH—C(═O)— K012J008 T151 329 —(CH₂)₂— —NH—C(═O)— K012 J009 T148 330 —(CH₂)₂— —NH—C(═O)—K012 J012 T148 331 —(CH₂)₂— —NH—C(═O)— K012 J025 T148 332 —(CH₂)₂——NH—C(═O)— K012 J025 T169 333 —(CH₂)₂— —NH—C(═O)— K012 J042 T148 334—(CH₂)₂— —NH—C(═O)— K012 J042 T152 335 —(CH₂)₂— —NH—C(═O)— K012 J045T148 336 —(CH₂)₂— —NH—C(═O)— K012 J059 T148 337 —(CH₂)₂— —NH—C(═O)— K012J059 T151 338 —(CH₂)₂— —NH—C(═O)— K012 J076 T148 339 —(CH₂)₂— —NH—C(═O)—K012 J076 T169 340 —(CH₂)₂— —NH—C(═O)— K012 J081 T164 341 —(CH₂)₂——NH—C(═O)— K013 J001 T168 342 —(CH₂)₂— —NH—C(═O)— K013 J008 T148 343—(CH₂)₂— —NH—C(═O)— K013 J012 T148 344 —(CH₂)₂— —NH—C(═O)— K013 J045T005 345 —(CH₂)₂— —NH—C(═O)— K013 J045 T077 346 —(CH₂)₂— —NH—C(═O)— K013J045 T090 347 —(CH₂)₂— —NH—C(═O)— K013 J045 T129 348 —(CH₂)₂— —NH—C(═O)—K013 J045 T148 349 —(CH₂)₂— —NH—C(═O)— K014 J002 T169 350 —(CH₂)₂——NH—C(═O)— K015 J008 T170 351 —(CH₂)₂— —NH—C(═O)— K016 J009 T173 352—(CH₂)₂— —NH—C(═O)— K017 J012 T176 353 —(CH₂)₂— —NH—C(═O)— K018 J014T178 354 —(CH₂)₂— —NH—C(═O)— K019 J015 T129 355 —(CH₂)₂— —NH—C(═O)— K020J018 T130 356 —(CH₂)₂— —NH—C(═O)— K021 J043 T134 357 —(CH₂)₂— —NH—C(═O)—K022 J045 T135 358 —(CH₂)₂— —NH—C(═O)— K023 J063 T145 359 —(CH₂)₂——NH—C(═O)— K024 J081 T148 360 —(CH₂)₂— —NH—C(═O)— K025 J001 T149 361—(CH₂)₂— —NH—C(═O)— K025 J045 T148 362 —(CH₂)₂— —NH—C(═O)— K026 J002T151 363 —(CH₂)₂— —NH—C(═O)— K027 J008 T152 364 —(CH₂)₂— —NH—C(═O)— K028J009 T157 365 —(CH₂)₂— —NH—C(═O)— K029 J012 T158 366 —(CH₂)₂— —NH—C(═O)—K030 J014 T164 367 —(CH₂)₂— —NH—C(═O)— K031 J015 T168 368 —(CH₂)₂——NH—C(═O)— K032 J018 T169 369 —(CH₂)₂— —NH—C(═O)— K033 J043 T170 370—(CH₂)₂— —NH—C(═O)— K033 J045 T004 371 —(CH₂)₂— —NH—C(═O)— K034 J045T173 372 —(CH₂)₂— —NH—C(═O)— K035 J063 T176 373 —(CH₂)₂— —NH—C(═O)— K036J081 T178 374 —(CH₂)₂— —NH—C(═O)— K037 J001 T129 375 —(CH₂)₂— —NH—C(═O)—K038 J002 T130 376 —(CH₂)₂— —NH—C(═O)— K039 J008 T134 377 —(CH₂)₂——NH—C(═O)— K040 J009 T135 378 —(CH₂)₂— —NH—C(═O)— K041 J012 T145 379—(CH₂)₂— —NH—C(═O)— K042 J014 T148 380 —(CH₂)₂— —NH—C(═O)— K043 J015T149 381 —(CH₂)₂— —NH—C(═O)— K044 J010 T148 382 —(CH₂)₂— —NH—C(═O)— K044J010 T169 383 —(CH₂)₂— —NH—C(═O)— K044 J018 T151 384 —(CH₂)₂— —NH—C(═O)—K044 J027 T148 385 —(CH₂)₂— —NH—C(═O)— K044 J027 T152 386 —(CH₂)₂——NH—C(═O)— K044 J044 T148 387 —(CH₂)₂— —NH—C(═O)— K044 J044 T151 388—(CH₂)₂— —NH—C(═O)— K044 J061 T148 389 —(CH₂)₂— —NH—C(═O)— K044 J061T169 390 —(CH₂)₂— —NH—C(═O)— K044 J078 T148 391 —(CH₂)₂— —NH—C(═O)— K044J078 T152 392 —(CH₂)₂— —NH—C(═O)— K045 J043 T152 393 —(CH₂)₂— —NH—C(═O)—K046 J045 T157 394 —(CH₂)₂— —NH—C(═O)— K047 J063 T158 395 —(CH₂)₂——NH—C(═O)— K048 J081 T164 396 —(CH₂)₂— —NH—C(═O)— K049 J001 T168 397—(CH₂)₂— —NH—C(═O)— K050 J002 T169 398 —(CH₂)₂— —NH—C(═O)— K051 J008T170 399 —(CH₂)₂— —NH—C(═O)— K052 J009 T173 400 —(CH₂)₂— —NH—C(═O)— K053J012 T176 401 —(CH₂)₂— —NH—C(═O)— K054 J014 T178 402 —(CH₂)₂— —NH—C(═O)—K055 J015 T129 403 —(CH₂)₂— —NH—C(═O)— K056 J018 T130 404 —(CH₂)₂——NH—C(═O)— K057 J043 T134 405 —(CH₂)₂— —NH—C(═O)— K058 J045 T135 406—(CH₂)₂— —NH—C(═O)— K059 J063 T145 407 —(CH₂)₂— —NH—C(═O)— K060 J081T148 408 —(CH₂)₂— —NH—C(═O)— K061 J001 T149 409 —(CH₂)₂— —NH—C(═O)— K062J002 T151 410 —(CH₂)₂— —NH—C(═O)— K063 J008 T152 411 —(CH₂)₂— —NH—C(═O)—K064 J009 T157 412 —(CH₂)₂— —NH—C(═O)— K065 J012 T158 413 —(CH₂)₂——NH—C(═O)— K066 J014 T164 414 —(CH₂)₂— —NH—C(═O)— K067 J015 T168 415—(CH₂)₂— —NH—C(═O)— K068 J018 T169 416 —(CH₂)₂— —NH—C(═O)— K069 J043T170 417 —(CH₂)₂— —NH—C(═O)— K070 J011 T148 418 —(CH₂)₂— —NH—C(═O)— K070J011 T151 419 —(CH₂)₂— —NH—C(═O)— K070 J028 T148 420 —(CH₂)₂— —NH—C(═O)—K070 J028 T169 421 —(CH₂)₂— —NH—C(═O)— K070 J045 T148 422 —(CH₂)₂——NH—C(═O)— K070 J045 T152 423 —(CH₂)₂— —NH—C(═O)— K070 J045 T173 424—(CH₂)₂— —NH—C(═O)— K070 J062 T148 425 —(CH₂)₂— —NH—C(═O)— K070 J062T151 426 —(CH₂)₂— —NH—C(═O)— K070 J079 T148 427 —(CH₂)₂— —NH—C(═O)— K070J079 T169 428 —(CH₂)₂— —NH—C(═O)— K071 J063 T176 429 —(CH₂)₂— —NH—C(═O)—K072 J012 T148 430 —(CH₂)₂— —NH—C(═O)— K072 J012 T152 431 —(CH₂)₂——NH—C(═O)— K072 J029 T148 432 —(CH₂)₂— —NH—C(═O)— K072 J029 T151 433—(CH₂)₂— —NH—C(═O)— K072 J046 T148 434 —(CH₂)₂— —NH—C(═O)— K072 J046T169 435 —(CH₂)₂— —NH—C(═O)— K072 J063 T148 436 —(CH₂)₂— —NH—C(═O)— K072J063 T152 437 —(CH₂)₂— —NH—C(═O)— K072 J080 T148 438 —(CH₂)₂— —NH—C(═O)—K072 J080 T151 439 —(CH₂)₂— —NH—C(═O)— K072 J081 T178 440 —(CH₂)₂——NH—C(═O)— K073 J001 T129 441 —(CH₂)₂— —NH—C(═O)— K074 J002 T130 442—(CH₂)₂— —NH—C(═O)— K075 J008 T134 443 —(CH₂)₂— —NH—C(═O)— K076 J009T135 444 —(CH₂)₂— —NH—C(═O)— K077 J012 T145 445 —(CH₂)₂— —NH—C(═O)— K078J014 T148 446 —(CH₂)₂— —NH—C(═O)— K079 J015 T149 447 —(CH₂)₂— —NH—C(═O)—K080 J018 T151 448 —(CH₂)₂— —NH—C(═O)— K081 J043 T152 449 —(CH₂)₂——NH—C(═O)— K082 J045 T157 450 —(CH₂)₂— —NH—C(═O)— K083 J063 T158 451—(CH₂)₂— —NH—C(═O)— K084 J081 T164 452 —(CH₂)₂— —NH—C(═O)— K085 J001T168 453 —(CH₂)₂— —NH—C(═O)— K086 J002 T169 454 —(CH₂)₂— —NH—C(═O)— K087J008 T170 455 —(CH₂)₂— —NH—C(═O)— K088 J009 T173 456 —(CH₂)₂— —NH—C(═O)—K089 J012 T176 457 —(CH₂)₂— —NH—C(═O)— K090 J014 T178 458 —(CH₂)₂——NH—C(═O)— K091 J015 T129 459 —(CH₂)₂— —NH—C(═O)— K092 J018 T130 460—(CH₂)₂— —NH—C(═O)— K093 J043 T134 461 —(CH₂)₂— —NH—C(═O)— K094 J045T135 462 —(CH₂)₂— —NH—C(═O)— K095 J063 T145 463 —(CH₂)₂— —NH—C(═O)— K096J081 T148 464 —(CH₂)₂— —NH—C(═O)— K097 J001 T149 465 —(CH₂)₂— —NH—C(═O)—K098 J002 T151 466 —(CH₂)₂— —NH—C(═O)— K099 J008 T152 467 —(CH₂)₂——NH—C(═O)— K100 J009 T157 468 —(CH₂)₂— —NH—C(═O)— K101 J012 T158 469—(CH₂)₂— —NH—C(═O)— K102 J014 T164 470 —(CH₂)₂— —NH—C(═O)— K103 J015T168 471 —(CH₂)₂— —NH—C(═O)— K104 J018 T169 472 —(CH₂)₂— —NH—C(═O)— K105J043 T170 473 —(CH₂)₂— —NH—C(═O)— K106 J045 T173 474 —(CH₂)₂— —NH—C(═O)—K107 J013 T148 475 —(CH₂)₂— —NH—C(═O)— K107 J013 T169 476 —(CH₂)₂——NH—C(═O)— K107 J030 T148 477 —(CH₂)₂— —NH—C(═O)— K107 J030 T152 478—(CH₂)₂— —NH—C(═O)— K107 J047 T148 479 —(CH₂)₂— —NH—C(═O)— K107 J047T151 480 —(CH₂)₂— —NH—C(═O)— K107 J063 T176 481 —(CH₂)₂— —NH—C(═O)— K107J064 T148 482 —(CH₂)₂— —NH—C(═O)— K107 J064 T169 483 —(CH₂)₂— —NH—C(═O)—K107 J081 T148 484 —(CH₂)₂— —NH—C(═O)— K107 J081 T152 485 —(CH₂)₂——NH—C(═O)— K108 J008 T148 486 —(CH₂)₂— —NH—C(═O)— K108 J009 T148 487—(CH₂)₂— —NH—C(═O)— K108 J012 T148 488 —(CH₂)₂— —NH—C(═O)— K108 J014T148 489 —(CH₂)₂— —NH—C(═O)— K108 J014 T151 490 —(CH₂)₂— —NH—C(═O)— K108J031 T148 491 —(CH₂)₂— —NH—C(═O)— K108 J031 T169 492 —(CH₂)₂— —NH—C(═O)—K108 J045 T148 493 —(CH₂)₂— —NH—C(═O)— K108 J048 T148 494 —(CH₂)₂——NH—C(═O)— K108 J048 T152 495 —(CH₂)₂— —NH—C(═O)— K108 J065 T148 496—(CH₂)₂— —NH—C(═O)— K108 J065 T151 497 —(CH₂)₂— —NH—C(═O)— K108 J081T178 498 —(CH₂)₂— —NH—C(═O)— K108 J082 T148 499 —(CH₂)₂— —NH—C(═O)— K108J082 T169 500 —(CH₂)₂— —NH—C(═O)— K109 J001 T129 501 —(CH₂)₂— —NH—C(═O)—K109 J008 T148 502 —(CH₂)₂— —NH—C(═O)— K109 J009 T148 503 —(CH₂)₂——NH—C(═O)— K109 J012 T148 504 —(CH₂)₂— —NH—C(═O)— K109 J045 T148 505—(CH₂)₂— —NH—C(═O)— K110 J002 T130 506 —(CH₂)₂— —NH—C(═O)— K111 J008T134 507 —(CH₂)₂— —NH—C(═O)— K112 J009 T135 508 —(CH₂)₂— —NH—C(═O)— K113J012 T145 509 —(CH₂)₂— —NH—C(═O)— K114 J014 T148 510 —(CH₂)₂— —NH—C(═O)—K115 J015 T149 511 —(CH₂)₂— —NH—C(═O)— K116 J018 T151 512 —(CH₂)₂——NH—C(═O)— K117 J043 T152 513 —(CH₂)₂— —NH—C(═O)— K118 J045 T157 514—(CH₂)₂— —NH—C(═O)— K119 J063 T158 515 —(CH₂)₂— —NH—C(═O)— K120 J081T164 516 —(CH₂)₂— —NH—C(═O)— K121 J001 T168 517 —(CH₂)₂— —NH—C(═O)— K122J002 T169 518 —(CH₂)₂— —NH—C(═O)— K123 J008 T170 519 —(CH₂)₂— —NH—C(═O)—K124 J009 T173 520 —(CH₂)₂— —NH—C(═O)— K125 J012 T176 521 —(CH₂)₂——NH—C(═O)— K126 J014 T178 522 —(CH₂)₂— —NH—C(═O)— K127 J015 T129 523—(CH₂)₂— —NH—C(═O)— K128 J018 T130 524 —(CH₂)₂— —NH—C(═O)— K129 J043T134 525 —(CH₂)₂— —NH—C(═O)— K130 J045 T135 526 —(CH₂)₂— —NH—C(═O)— K131J063 T145 527 —(CH₂)₂— —NH—C(═O)— K132 J081 T148 528 —(CH₂)₂— —NH—C(═O)—K133 J001 T149 529 —(CH₂)₂— —NH—C(═O)— K134 J002 T151 530 —(CH₂)₂——NH—C(═O)— K135 J008 T152 531 —(CH₂)₂— —NH—C(═O)— K136 J009 T157 532—(CH₂)₂— —NH—C(═O)— K137 J008 T148 533 —(CH₂)₂— —NH—C(═O)— K137 J009T148 534 —(CH₂)₂— —NH—C(═O)— K137 J012 T148 535 —(CH₂)₂— —NH—C(═O)— K137J012 T158 536 —(CH₂)₂— —NH—C(═O)— K137 J045 T148 537 —(CH₂)₂— —NH—C(═O)—K138 J014 T164 538 —(CH₂)₂— —NH—C(═O)— K139 J015 T168 539 —(CH₂)₂——NH—C(═O)— K140 J018 T169 540 —(CH₂)₂— —NH—C(═O)— K141 J043 T170 541—(CH₂)₂— —NH—C(═O)— K142 J045 T173 542 —(CH₂)₂— —NH—C(═O)— K143 J063T176 543 —(CH₂)₂— —NH—C(═O)— K144 J008 T148 544 —(CH₂)₂— —NH—C(═O)— K144J009 T148 545 —(CH₂)₂— —NH—C(═O)— K144 J012 T148 546 —(CH₂)₂— —NH—C(═O)—K144 J015 T148 547 —(CH₂)₂— —NH—C(═O)— K144 J015 T152 548 —(CH₂)₂——NH—C(═O)— K144 J032 T148 549 —(CH₂)₂— —NH—C(═O)— K144 J032 T151 550—(CH₂)₂— —NH—C(═O)— K144 J045 T148 551 —(CH₂)₂— —NH—C(═O)— K144 J049T148 552 —(CH₂)₂— —NH—C(═O)— K144 J049 T169 553 —(CH₂)₂— —NH—C(═O)— K144J066 T148 554 —(CH₂)₂— —NH—C(═O)— K144 J066 T152 555 —(CH₂)₂— —NH—C(═O)—K144 J081 T178 556 —(CH₂)₂— —NH—C(═O)— K144 J083 T148 557 —(CH₂)₂——NH—C(═O)— K144 J083 T151 558 —(CH₂)₂— —NH—C(═O)— K145 J001 T129 559—(CH₂)₂— —NH—C(═O)— K146 J002 T130 560 —(CH₂)₂— —NH—C(═O)— K147 J008T134 561 —(CH₂)₂— —NH—C(═O)— K148 J009 T135 562 —(CH₂)₂— —NH—C(═O)— K149J012 T145 563 —(CH₂)₂— —NH—C(═O)— K150 J014 T148 564 —(CH₂)₂— —NH—C(═O)—K151 J015 T149 565 —(CH₂)₂— —NH—C(═O)— K152 J018 T151 566 —(CH₂)₂——NH—C(═O)— K153 J043 T152 567 —(CH₂)₂— —NH—C(═O)— K154 J045 T157 568—(CH₂)₂— —NH—C(═O)— K155 J063 T158 569 —(CH₂)₂— —NH—C(═O)— K156 J081T164 570 —(CH₂)₂— —NH—C(═O)— K157 J001 T168 571 —(CH₂)₂— —NH—C(═O)— K158J002 T169 572 —(CH₂)₂— —NH—C(═O)— K159 J008 T170 573 —(CH₂)₂— —NH—C(═O)—K160 J009 T173 574 —(CH₂)₂— —NH—C(═O)— K161 J012 T176 575 —(CH₂)₂——NH—C(═O)— K162 J014 T178 576 —(CH₂)₂— —NH—C(═O)— K163 J015 T129 577—(CH₂)₂— —NH—C(═O)— K164 J018 T130 578 —(CH₂)₂— —NH—C(═O)— K165 J043T134 579 —(CH₂)₂— —NH—C(═O)— K166 J045 T135 580 —(CH₂)₂— —NH—C(═O)— K167J063 T145 581 —(CH₂)₂— —NH—C(═O)— K168 J081 T148 582 —(CH₂)₂— —NH—C(═O)—K169 J001 T149 583 —(CH₂)₂— —NH—C(═O)— K170 J002 T151 584 —(CH₂)₂——NH—C(═O)— K171 J008 T152 585 —(CH₂)₂— —NH—C(═O)— K172 J009 T157 586—(CH₂)₂— —NH—C(═O)— K173 J012 T158 587 —(CH₂)₂— —NH—C(═O)— K174 J014T164 588 —(CH₂)₂— —NH—C(═O)— K175 J015 T168 589 —(CH₂)₂— —NH—C(═O)— K176J018 T169 590 —(CH₂)₂— —NH—C(═O)— K177 J043 T170 591 —(CH₂)₂— —NH—C(═O)—K178 J045 T173 592 —(CH₂)₂— —NH—C(═O)— K197 J063 T176 593 —(CH₂)₂——NH—C(═O)— K198 J008 T148 594 —(CH₂)₂— —NH—C(═O)— K198 J009 T148 595—(CH₂)₂— —NH—C(═O)— K198 J012 T148 596 —(CH₂)₂— —NH—C(═O)— K198 J045T148 597 —(CH₂)₂— —NH—C(═O)— K198 J081 T178 598 —(CH₂)₂— —NH—C(═O)— K199J001 T129 599 —(CH₂)₂— —NH—C(═O)— K199 J008 T148 600 —(CH₂)₂— —NH—C(═O)—K199 J009 T148 601 —(CH₂)₂— —NH—C(═O)— K199 J012 T148 602 —(CH₂)₂——NH—C(═O)— K199 J045 T148 603 —(CH₂)₂— —NH—C(═O)— K200 J002 T130 604—(CH₂)₂— —NH—C(═O)— K200 J008 T005 605 —(CH₂)₂— —NH—C(═O)— K200 J008T148 606 —(CH₂)₂— —NH—C(═O)— K200 J008 T151 607 —(CH₂)₂— —NH—C(═O)— K200J008 T152 608 —(CH₂)₂— —NH—C(═O)— K200 J008 T169 609 —(CH₂)₂— —NH—C(═O)—K200 J009 T005 610 —(CH₂)₂— —NH—C(═O)— K200 J009 T148 611 —(CH₂)₂——NH—C(═O)— K200 J009 T151 612 —(CH₂)₂— —NH—C(═O)— K200 J009 T152 613—(CH₂)₂— —NH—C(═O)— K200 J009 T169 614 —(CH₂)₂— —NH—C(═O)— K200 J012T005 615 —(CH₂)₂— —NH—C(═O)— K200 J012 T148 616 —(CH₂)₂— —NH—C(═O)— K200J012 T151 617 —(CH₂)₂— —NH—C(═O)— K200 J012 T152 618 —(CH₂)₂— —NH—C(═O)—K200 J012 T169 619 —(CH₂)₂— —NH—C(═O)— K200 J016 T005 620 —(CH₂)₂——NH—C(═O)— K200 J016 T148 621 —(CH₂)₂— —NH—C(═O)— K200 J016 T169 622—(CH₂)₂— —NH—C(═O)— K200 J033 T005 623 —(CH₂)₂— —NH—C(═O)— K200 J033T148 624 —(CH₂)₂— —NH—C(═O)— K200 J033 T152 625 —(CH₂)₂— —NH—C(═O)— K200J045 T005 626 —(CH₂)₂— —NH—C(═O)— K200 J045 T148 627 —(CH₂)₂— —NH—C(═O)—K200 J045 T151 628 —(CH₂)₂— —NH—C(═O)— K200 J045 T152 629 —(CH₂)₂——NH—C(═O)— K200 J045 T169 630 —(CH₂)₂— —NH—C(═O)— K200 J050 T148 631—(CH₂)₂— —NH—C(═O)— K200 J050 T151 632 —(CH₂)₂— —NH—C(═O)— K200 J067T148 633 —(CH₂)₂— —NH—C(═O)— K200 J067 T169 634 —(CH₂)₂— —NH—C(═O)— K200J084 T148 635 —(CH₂)₂— —NH—C(═O)— K200 J084 T152 636 —(CH₂)₂— —NH—C(═O)—K201 J008 T134 637 —(CH₂)₂— —NH—C(═O)— K202 J009 T135 638 —(CH₂)₂——NH—C(═O)— K203 J008 T148 639 —(CH₂)₂— —NH—C(═O)— K203 J009 T148 640—(CH₂)₂— —NH—C(═O)— K203 J012 T145 641 —(CH₂)₂— —NH—C(═O)— K203 J012T148 642 —(CH₂)₂— —NH—C(═O)— K203 J017 T148 643 —(CH₂)₂— —NH—C(═O)— K203J017 T151 644 —(CH₂)₂— —NH—C(═O)— K203 J034 T148 645 —(CH₂)₂— —NH—C(═O)—K203 J034 T169 646 —(CH₂)₂— —NH—C(═O)— K203 J045 T148 647 —(CH₂)₂——NH—C(═O)— K203 J051 T148 648 —(CH₂)₂— —NH—C(═O)— K203 J051 T152 649—(CH₂)₂— —NH—C(═O)— K203 J068 T148 650 —(CH₂)₂— —NH—C(═O)— K203 J068T151 651 —(CH₂)₂— —NH—C(═O)— K203 J085 T148 652 —(CH₂)₂— —NH—C(═O)— K203J085 T169 653 —(CH₂)₂— —NH—C(═O)— K204 J014 T148 654 —(CH₂)₂— —NH—C(═O)—K205 J015 T149 655 —(CH₂)₂— —NH—C(═O)— K206 J008 T148 656 —(CH₂)₂——NH—C(═O)— K206 J009 T148 657 —(CH₂)₂— —NH—C(═O)— K206 J012 T148 658—(CH₂)₂— —NH—C(═O)— K206 J018 T151 659 —(CH₂)₂— —NH—C(═O)— K206 J045T148 660 —(CH₂)₂— —NH—C(═O)— K207 J008 T148 661 —(CH₂)₂— —NH—C(═O)— K207J009 T148 662 —(CH₂)₂— —NH—C(═O)— K207 J012 T148 663 —(CH₂)₂— —NH—C(═O)—K207 J043 T152 664 —(CH₂)₂— —NH—C(═O)— K207 J045 T148 665 —(CH₂)₂——NH—C(═O)— K208 J008 T148 666 —(CH₂)₂— —NH—C(═O)— K208 J009 T148 667—(CH₂)₂— —NH—C(═O)— K208 J012 T148 668 —(CH₂)₂— —NH—C(═O)— K208 J045T148 669 —(CH₂)₂— —NH—C(═O)— K208 J045 T157 670 —(CH₂)₂— —NH—C(═O)— K209J008 T148 671 —(CH₂)₂— —NH—C(═O)— K209 J009 T148 672 —(CH₂)₂— —NH—C(═O)—K209 J012 T148 673 —(CH₂)₂— —NH—C(═O)— K209 J045 T148 674 —(CH₂)₂——NH—C(═O)— K209 J063 T158 675 —(CH₂)₂— —NH—C(═O)— K210 J008 T148 676—(CH₂)₂— —NH—C(═O)— K210 J009 T148 677 —(CH₂)₂— —NH—C(═O)— K270 J012T148 678 —(CH₂)₂— —NH—C(═O)— K210 J045 T148 679 —(CH₂)₂— —NH—C(═O)— K210J081 T164 680 —(CH₂)₂— —NH—C(═O)— K211 J001 T168 681 —(CH₂)₂— —NH—C(═O)—K211 J008 T148 682 —(CH₂)₂— —NH—C(═O)— K211 J009 T148 683 —(CH₂)₂——NH—C(═O)— K211 J012 T148 684 —(CH₂)₂— —NH—C(═O)— K211 J045 T148 685—(CH₂)₂— —NH—C(═O)— K212 J002 T169 686 —(CH₂)₂— —NH—C(═O)— K212 J008T148 687 —(CH₂)₂— —NH—C(═O)— K212 J009 T148 688 —(CH₂)₂— —NH—C(═O)— K212J012 T148 689 —(CH₂)₂— —NH—C(═O)— K212 J045 T148 690 —(CH₂)₂— —NH—C(═O)—K213 J008 T170 691 —(CH₂)₂— —NH—C(═O)— K214 J009 T173 692 —(CH₂)₂——NH—C(═O)— K215 J008 T148 693 —(CH₂)₂— —NH—C(═O)— K215 J009 T148 694—(CH₂)₂— —NH—C(═O)— K215 J012 T148 695 —(CH₂)₂— —NH—C(═O)— K215 J012T176 696 —(CH₂)₂— —NH—C(═O)— K215 J045 T148 697 —(CH₂)₂— —NH—C(═O)— K216J014 T178 698 —(CH₂)₂— —NH—C(═O)— K217 J015 T129 699 —(CH₂)₂— —NH—C(═O)—K218 J018 T130 700 —(CH₂)₂— —NH—C(═O)— K219 J008 T148 701 —(CH₂)₂——NH—C(═O)— K219 J009 T148 702 —(CH₂)₂— —NH—C(═O)— K219 J012 T148 703—(CH₂)₂— —NH—C(═O)— K219 J043 T134 704 —(CH₂)₂— —NH—C(═O)— K219 J045T148 705 —(CH₂)₂— —NH—C(═O)— K220 J008 T148 706 —(CH₂)₂— —NH—C(═O)— K220J009 T148 707 —(CH₂)₂— —NH—C(═O)— K220 J012 T148 708 —(CH₂)₂— —NH—C(═O)—K220 J045 T135 709 —(CH₂)₂— —NH—C(═O)— K220 J045 T148 710 —(CH₂)₂——NH—C(═O)— K221 J008 T148 711 —(CH₂)₂— —NH—C(═O)— K221 J009 T148 712—(CH₂)₂— —NH—C(═O)— K221 J012 T148 713 —(CH₂)₂— —NH—C(═O)— K221 J045T148 714 —(CH₂)₂— —NH—C(═O)— K221 J063 T145 715 —(CH₂)₂— —NH—C(═O)— K222J008 T148 716 —(CH₂)₂— —NH—C(═O)— K222 J009 T148 717 —(CH₂)₂— —NH—C(═O)—K222 J012 T148 718 —(CH₂)₂— —NH—C(═O)— K222 J045 T148 719 —(CH₂)₂——NH—C(═O)— K222 J081 T148 720 —(CH₂)₂— —NH—C(═O)— K223 J001 T149 721—(CH₂)₂— —NH—C(═O)— K223 J008 T148 722 —(CH₂)₂— —NH—C(═O)— K223 J009T148 723 —(CH₂)₂— —NH—C(═O)— K223 J012 T148 724 —(CH₂)₂— —NH—C(═O)— K223J045 T148 725 —(CH₂)₂— —NH—C(═O)— K224 J002 T151 726 —(CH₂)₂— —NH—C(═O)—K224 J008 T148 727 —(CH₂)₂— —NH—C(═O)— K224 J009 T148 728 —(CH₂)₂——NH—C(═O)— K224 J012 T148 729 —(CH₂)₂— —NH—C(═O)— K224 J045 T148 730—(CH₂)₂— —NH—C(═O)— K225 J008 T148 731 —(CH₂)₂— —NH—C(═O)— K225 J008T152 732 —(CH₂)₂— —NH—C(═O)— K225 J009 T148 733 —(CH₂)₂— —NH—C(═O)— K225J012 T148 734 —(CH₂)₂— —NH—C(═O)— K225 J045 T148 735 —(CH₂)₂— —NH—C(═O)—K226 J009 T157 736 —(CH₂)₂— —NH—C(═O)— K227 J012 T158 737 —(CH₂)₂——NH—C(═O)— K228 J008 T148 738 —(CH₂)₂— —NH—C(═O)— K228 J009 T148 739—(CH₂)₂— —NH—C(═O)— K228 J012 T148 740 —(CH₂)₂— —NH—C(═O)— K228 J014T164 741 —(CH₂)₂— —NH—C(═O)— K228 J045 T148 742 —(CH₂)₂— —NH—C(═O)— K229J015 T168 743 —(CH₂)₂— —NH—C(═O)— K230 J018 T169 744 —(CH₂)₂— —NH—C(═O)—K231 J043 T170 745 —(CH₂)₂— —NH—C(═O)— K232 J045 T173 746 —(CH₂)₂——NH—C(═O)— K233 J063 T176 747 —(CH₂)₂— —NH—C(═O)— K234 J081 T178 748—(CH₂)₂— —NH—C(═O)— K235 J012 T148 749 —(CH₂)₂— —NH—C(═O)— K236 J045T148 750 —(CH₂)₂— —NH—C(═O)—NH— K003 J002 T148 751 —(CH₂)₂——NH—C(═O)—NH— K003 J002 T151 752 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T148753 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T151 754 —(CH₂)₂— —NH—C(═O)—NH—K003 J008 T152 755 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T169 756 —(CH₂)₂——NH—C(═O)—NH— K003 J009 T148 757 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T151758 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T152 759 —(CH₂)₂— —NH—C(═O)—NH—K003 J009 T169 760 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T148 761 —(CH₂)₂——NH—C(═O)—NH— K003 J012 T151 762 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T152763 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T169 764 —(CH₂)₂— —NH—C(═O)—NH—K003 J019 T148 765 —(CH₂)₂— —NH—C(═O)—NH— K003 J019 T169 766 —(CH₂)₂——NH—C(═O)—NH— K003 J036 T148 767 —(CH₂)₂— —NH—C(═O)—NH— K003 J036 T152768 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T148 769 —(CH₂)₂— —NH—C(═O)—NH—K003 J045 T151 770 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T152 771 —(CH₂)₂——NH—C(═O)—NH— K003 J045 T169 772 —(CH₂)₂— —NH—C(═O)—NH— K003 J053 T148773 —(CH₂)₂— —NH—C(═O)—NH— K003 J053 T151 774 —(CH₂)₂— —NH—C(═O)—NH—K003 J070 T148 775 —(CH₂)₂— —NH—C(═O)—NH— K003 J070 T169 776 —(CH₂)₂——NH—C(═O)—NH— K009 J045 T148 777 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T148778 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T151 779 —(CH₂)₂— —NH—C(═O)—NH—K012 J008 T152 780 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T169 781 —(CH₂)₂——NH—C(═O)—NH— K012 J009 T148 782 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T151783 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T152 784 —(CH₂)₂— —NH—C(═O)—NH—K012 J009 T169 785 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T148 786 —(CH₂)₂——NH—C(═O)—NH— K012 J012 T151 787 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T152788 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T169 789 —(CH₂)₂— —NH—C(═O)—NH—K012 J026 T148 790 —(CH₂)₂— —NH—C(═O)—NH— K012 J026 T151 791 —(CH₂)₂——NH—C(═O)—NH— K012 J043 T148 792 —(CH₂)₂— —NH—C(═O)—NH— K012 J043 T169793 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T148 794 —(CH₂)₂— —NH—C(═O)—NH—K012 J045 T151 795 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T152 796 —(CH₂)₂——NH—C(═O)—NH— K012 J045 T169 797 —(CH₂)₂— —NH—C(═O)—NH— K012 J060 T148798 —(CH₂)₂— —NH—C(═O)—NH— K012 J060 T152 799 —(CH₂)₂— —NH—C(═O)—NH—K012 J077 T148 800 —(CH₂)₂— —NH—C(═O)—NH— K012 J077 T151 801 —(CH₂)₂——NH—C(═O)—NH— K013 J045 T148 802 —(CH₂)₂— —NH—C(═O)—NH— K014 J045 T148803 —(CH₂)₂— —NH—C(═O)—NH— K017 J045 T148 804 —(CH₂)₂— —NH—C(═O)—NH—K032 J045 T148 805 —(CH₂)₂— —NH—C(═O)—NH— K229 J045 T148 806 —(CH₂)₂——NH—C(═O)—NH— K230 J045 T148 807 —(CH₂)₂— —NH—C(═O)—NH— K231 J045 T148808 —(CH₂)₂— —NH—C(═O)—NH— K232 J045 T148 809 —(CH₂)₂— —NH—C(═O)—NH—K233 J045 T148 810 —(CH₂)₂— —NH—C(═O)—NH— K234 J045 T148 811 —(CH₂)₂——NH—C(═O)—NH— K235 J045 T148 812 —(CH₂)₂— —NH—C(═O)—NH— K236 J045 T148813 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T001 814 —(CH₂)₂— —NH—C(═O)—O— K005J001 T005 815 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T010 816 —(CH₂)₂——NH—C(═O)—O— K005 J001 T019 817 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T028 818—(CH₂)₂— —NH—C(═O)—O— K005 J001 T037 819 —(CH₂)₂— —NH—C(═O)—O— K005 J001T046 820 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T055 821 —(CH₂)₂— —NH—C(═O)—O—K005 J001 T064 822 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T073 823 —(CH₂)₂——NH—C(═O)—O— K005 J001 T082 824 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T091 825—(CH₂)₂— —NH—C(═O)—O— K005 J001 T100 826 —(CH₂)₂— —NH—C(═O)—O— K005 J001T109 827 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T118 828 —(CH₂)₂— —NH—C(═O)—O—K005 J001 T127 829 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T136 830 —(CH₂)₂——NH—C(═O)—O— K005 J001 T145 831 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T154 832—(CH₂)₂— —NH—C(═O)—O— K005 J001 T163 833 —(CH₂)₂— —NH—C(═O)—O— K005 J001T172 834 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T002 835 —(CH₂)₂— —NH—C(═O)—O—K005 J002 T011 836 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T020 837 —(CH₂)₂——NH—C(═O)—O— K005 J002 T029 838 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T038 839—(CH₂)₂— —NH—C(═O)—O— K005 J002 T047 840 —(CH₂)₂— —NH—C(═O)—O— K005 J002T056 841 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T065 842 —(CH₂)₂— —NH—C(═O)—O—K005 J002 T074 843 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T083 844 —(CH₂)₂——NH—C(═O)—O— K005 J002 T092 845 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T101 846—(CH₂)₂— —NH—C(═O)—O— K005 J002 T110 847 —(CH₂)₂— —NH—C(═O)—O— K005 J002T119 848 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T128 849 —(CH₂)₂— —NH—C(═O)—O—K005 J002 T137 850 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T146 851 —(CH₂)₂——NH—C(═O)—O— K005 J002 T155 852 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T164 853—(CH₂)₂— —NH—C(═O)—O— K005 J002 T173 854 —(CH₂)₂— —NH—C(═O)—O— K005 J008T003 855 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T005 856 —(CH₂)₂— —NH—C(═O)—O—K005 J008 T012 857 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T021 858 —(CH₂)₂——NH—C(═O)—O— K005 J008 T030 859 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T039 860—(CH₂)₂— —NH—C(═O)—O— K005 J008 T048 861 —(CH₂)₂— —NH—C(═O)—O— K005 J008T057 862 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T066 863 —(CH₂)₂— —NH—C(═O)—O—K005 J008 T075 864 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T084 865 —(CH₂)₂——NH—C(═O)—O— K005 J008 T093 866 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T102 867—(CH₂)₂— —NH—C(═O)—O— K005 J008 T111 868 —(CH₂)₂— —NH—C(═O)—O— K005 J008T120 869 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T129 870 —(CH₂)₂— —NH—C(═O)—O—K005 J008 T138 871 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T147 872 —(CH₂)₂——NH—C(═O)—O— K005 J008 T156 873 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T165 874—(CH₂)₂— —NH—C(═O)—O— K005 J008 T174 875 —(CH₂)₂— —NH—C(═O)—O— K005 J009T004 876 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T005 877 —(CH₂)₂— —NH—C(═O)—O—K005 J009 T013 878 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T022 879 —(CH₂)₂——NH—C(═O)—O— K005 J009 T031 880 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T040 881—(CH₂)₂— —NH—C(═O)—O— K005 J009 T049 882 —(CH₂)₂— —NH—C(═O)—O— K005 J009T058 883 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T067 884 —(CH₂)₂— —NH—C(═O)—O—K005 J009 T076 885 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T085 886 —(CH₂)₂——NH—C(═O)—O— K005 J009 T094 887 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T103 888—(CH₂)₂— —NH—C(═O)—O— K005 J009 T112 889 —(CH₂)₂— —NH—C(═O)—O— K005 J009T121 890 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T130 891 —(CH₂)₂— —NH—C(═O)—O—K005 J009 T139 892 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T148 893 —(CH₂)₂——NH—C(═O)—O— K005 J009 T157 894 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T166 895—(CH₂)₂— —NH—C(═O)—O— K005 J009 T175 896 —(CH₂)₂— —NH—C(═O)—O— K005 J012T005 897 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T014 898 —(CH₂)₂— —NH—C(═O)—O—K005 J012 T017 899 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T023 900 —(CH₂)₂——NH—C(═O)—O— K005 J012 T032 901 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T041 902—(CH₂)₂— —NH—C(═O)—O— K005 J012 T050 903 —(CH₂)₂— —NH—C(═O)—O— K005 J012T055 904 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T059 905 —(CH₂)₂— —NH—C(═O)—O—K005 J012 T068 906 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T077 907 —(CH₂)₂——NH—C(═O)—O— K005 J012 T086 908 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T095 909—(CH₂)₂— —NH—C(═O)—O— K005 J012 T104 910 —(CH₂)₂— —NH—C(═O)—O— K005 J012T113 911 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T122 912 —(CH₂)₂— —NH—C(═O)—O—K005 J012 T129 913 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T131 914 —(CH₂)₂——NH—C(═O)—O— K005 J012 T140 915 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T148 916—(CH₂)₂— —NH—C(═O)—O— K005 J012 T149 917 —(CH₂)₂— —NH—C(═O)—O— K005 J012T151 918 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T152 919 —(CH₂)₂— —NH—C(═O)—O—K005 J012 T158 920 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T167 921 —(CH₂)₂——NH—C(═O)—O— K005 J012 T176 922 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T005 923—(CH₂)₂— —NH—C(═O)—O— K005 J043 T006 924 —(CH₂)₂— —NH—C(═O)—O— K005 J043T015 925 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T024 926 —(CH₂)₂— —NH—C(═O)—O—K005 J043 T033 927 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T042 928 —(CH₂)₂——NH—C(═O)—O— K005 J043 T051 929 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T060 930—(CH₂)₂— —NH—C(═O)—O— K005 J043 T069 931 —(CH₂)₂— —NH—C(═O)—O— K005 J043T078 932 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T087 933 —(CH₂)₂— —NH—C(═O)—O—K005 J043 T096 934 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T105 935 —(CH₂)₂——NH—C(═O)—O— K005 J043 T114 936 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T123 937—(CH₂)₂— —NH—C(═O)—O— K005 J043 T132 938 —(CH₂)₂— —NH—C(═O)—O— K005 J043T141 939 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T150 940 —(CH₂)₂— —NH—C(═O)—O—K005 J043 T159 941 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T168 942 —(CH₂)₂——NH—C(═O)—O— K005 J043 T177 943 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T001 944—(CH₂)₂— —NH—C(═O)—O— K005 J045 T003 945 —(CH₂)₂— —NH—C(═O)—O— K005 J045T004 946 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T005 947 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T007 948 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T008 949 —(CH₂)₂——NH—C(═O)—O— K005 J045 T016 950 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T017 951—(CH₂)₂— —NH—C(═O)—O— K005 J045 T018 952 —(CH₂)₂— —NH—C(═O)—O— K005 J045T019 953 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T020 954 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T025 955 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T034 956 —(CH₂)₂——NH—C(═O)—O— K005 J045 T042 957 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T043 958—(CH₂)₂— —NH—C(═O)—O— K005 J045 T052 959 —(CH₂)₂— —NH—C(═O)—O— K005 J045T055 960 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T061 961 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T070 962 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T077 963 —(CH₂)₂——NH—C(═O)—O— K005 J045 T079 964 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T088 965—(CH₂)₂— —NH—C(═O)—O— K005 J045 T090 966 —(CH₂)₂— —NH—C(═O)—O— K005 J045T096 967 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T097 968 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T100 969 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T106 970 —(CH₂)₂——NH—C(═O)—O— K005 J045 T108 971 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T110 972—(CH₂)₂— —NH—C(═O)—O— K005 J045 T111 973 —(CH₂)₂— —NH—C(═O)—O— K005 J045T114 974 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T115 975 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T116 976 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T118 977 —(CH₂)₂——NH—C(═O)—O— K005 J045 T119 978 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T121 979—(CH₂)₂— —NH—C(═O)—O— K005 J045 T122 980 —(CH₂)₂— —NH—C(═O)—O— K005 J045T123 981 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T124 982 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T128 983 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T129 984 —(CH₂)₂——NH—C(═O)—O— K005 J045 T130 985 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T133 986—(CH₂)₂— —NH—C(═O)—O— K005 J045 T136 987 —(CH₂)₂— —NH—C(═O)—O— K005 J045T137 988 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T138 989 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T139 990 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T140 991 —(CH₂)₂——NH—C(═O)—O— K005 J045 T141 992 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T142 993—(CH₂)₂— —NH—C(═O)—O— K005 J045 T143 994 —(CH₂)₂— —NH—C(═O)—O— K005 J045T144 995 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T145 996 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T146 997 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T147 998 —(CH₂)₂——NH—C(═O)—O— K005 J045 T148 999 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T1491000 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T150 1001 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T151 1002 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T152 1003 —(CH₂)₂——NH—C(═O)—O— K005 J045 T153 1004 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T1541005 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T155 1006 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T156 1007 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T157 1008 —(CH₂)₂——NH—C(═O)—O— K005 J045 T158 1009 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T1591010 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T160 1011 —(CH₂)₂— —NH—C(═O)—O—K005 J045 T162 1012 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T163 1013 —(CH₂)₂——NH—C(═O)—O— K005 J045 T167 1014 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T1691015 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T178 1016 —(CH₂)₂— —NH—C(═O)—O—K005 J063 T008 1017 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T017 1018 —(CH₂)₂——NH—C(═O)—O— K005 J063 T026 1019 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T0351020 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T044 1021 —(CH₂)₂— —NH—C(═O)—O—K005 J063 T053 1022 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T062 1023 —(CH₂)₂——NH—C(═O)—O— K005 J063 T071 1024 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T0801025 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T089 1026 —(CH₂)₂— —NH—C(═O)—O—K005 J063 T098 1027 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T107 1028 —(CH₂)₂——NH—C(═O)—O— K005 J063 T116 1029 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T1251030 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T134 1031 —(CH₂)₂— —NH—C(═O)—O—K005 J063 T143 1032 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T152 1033 —(CH₂)₂——NH—C(═O)—O— K005 J063 T161 1034 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T1701035 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T179 1036 —(CH₂)₂— —NH—C(═O)—O—K005 J081 T009 1037 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T018 1038 —(CH₂)₂——NH—C(═O)—O— K005 J081 T027 1039 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T0361040 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T045 1041 —(CH₂)₂— —NH—C(═O)—O—K005 J081 T054 1042 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T063 1043 —(CH₂)₂——NH—C(═O)—O— K005 J081 T072 1044 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T0811045 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T090 1046 —(CH₂)₂— —NH—C(═O)—O—K005 J081 T099 1047 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T108 1048 —(CH₂)₂——NH—C(═O)—O— K005 J081 T117 1049 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T1261050 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T135 1051 —(CH₂)₂— —NH—C(═O)—O—K005 J081 T144 1052 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T153 1053 —(CH₂)₂——NH—C(═O)—O— K005 J081 T162 1054 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T1711055 —(CH₂)₂— Single bond K179 J012 T148 1056 —(CH₂)₂— Single bond K180J045 T148 1057 —(CH₂)₂— Single bond K239 J045 T148 1058 —(CH₂)₃— —C(═O)—K002 J001 T151 1059 —(CH₂)₃— —C(═O)— K002 J012 T151 1060 —(CH₂)₃——C(═O)— K003 J001 T151 1061 —(CH₂)₃— —C(═O)— K003 J012 T151 1062—(CH₂)₃— —C(═O)— K004 J001 T151 1063 —(CH₂)₃— —C(═O)— K004 J012 T1511064 —(CH₂)₃— —C(═O)— K005 J001 T151 1065 —(CH₂)₃— —C(═O)— K005 J012T151 1066 —(CH₂)₃— —C(═O)— K007 J001 T152 1067 —(CH₂)₃— —C(═O)— K007J012 T152 1068 —(CH₂)₃— —C(═O)— K008 J001 T152 1069 —(CH₂)₃— —C(═O)—K008 J012 T152 1070 —(CH₂)₃— —C(═O)— K009 J001 T152 1071 —(CH₂)₃——C(═O)— K009 J012 T152 1072 —(CH₂)₃— —C(═O)— K012 J001 T152 1073—(CH₂)₃— —C(═O)— K012 J012 T152 1074 —(CH₂)₃— —C(═O)— K107 J001 T1681075 —(CH₂)₃— —C(═O)— K107 J012 T169 1076 —(CH₂)₃— —C(═O)— K108 J001T169 1077 —(CH₂)₃— —C(═O)— K108 J012 T169 1078 —(CH₂)₃— —C(═O)— K112J001 T170 1079 —(CH₂)₃— —C(═O)— K112 J012 T169 1080 —(CH₂)₃— —C(═O)—K129 J001 T171 1081 —(CH₂)₃— —C(═O)— K129 J012 T169 1082 —(CH₂)₃——C(═O)— K133 J001 T172 1083 —(CH₂)₃— —C(═O)— K133 J012 T169 1084—(CH₂)₃— —C(═O)— K137 J001 T173 1085 —(CH₂)₃— —C(═O)— K137 J012 T1691086 —(CH₂)₃— —C(═O)—O— K001 J001 T148 1087 —(CH₂)₃— —C(═O)—O— K002 J001T151 1088 —(CH₂)₃— —C(═O)—O— K193 J001 T152 1089 —(CH₂)₃— —C(═O)—O— K227J001 T169 1090 —(CH₂)₃— —NH— K185 J045 T151 1091 —(CH₂)₃— —NH— K185 J045T169 1092 —(CH₂)₃— —NH—C(═O)— K008 J012 T151 1093 —(CH₂)₃— —NH—C(═O)—K008 J012 T169 1094 —(CH₂)₃— —NH—C(═O)— K013 J001 T151 1095 —(CH₂)₃——NH—C(═O)— K013 J001 T169 1096 —(CH₂)₃— —NH—C(═O)— K200 J045 T148 1097—(CH₂)₃— —NH—C(═O)— K200 J045 T152 1098 —(CH₂)₃— —NH—C(═O)—NH— K003 J012T148 1099 —(CH₂)₃— —NH—C(═O)—NH— K003 J012 T152 1100 —(CH₂)₃——NH—C(═O)—O— K005 J001 T148 1101 —(CH₂)₃— —NH—C(═O)—O— K005 J001 T1521102 —CH₂— —C(═O)— K107 J001 T148 1103 —CH₂— —C(═O)— K107 J012 T148 1104—CH₂— —C(═O)— K107 J018 T148 1105 —CH₂— —C(═O)— K108 J001 T129 1106—CH₂— —C(═O)— K108 J001 T148 1107 —CH₂— —C(═O)— K108 J001 T151 1108—CH₂— —C(═O)— K108 J001 T152 1109 —CH₂— —C(═O)— K108 J001 T164 1110—CH₂— —C(═O)— K108 J001 T170 1111 —CH₂— —C(═O)— K108 J001 T171 1112—CH₂— —C(═O)— K108 J012 T148 1113 —CH₂— —C(═O)— K108 J022 T148 1114—CH₂— —C(═O)— K112 J001 T148 1115 —CH₂— —C(═O)— K112 J012 T148 1116—CH₂— —C(═O)— K129 J001 T148 1117 —CH₂— —C(═O)— K129 J012 T148 1118—CH₂— —C(═O)— K129 J014 T148 1119 —CH₂— —C(═O)— K133 J001 T148 1120—CH₂— —C(═O)— K133 J008 T148 1121 —CH₂— —C(═O)— K133 J012 T148 1122—CH₂— —C(═O)— K137 J001 T129 1123 —CH₂— —C(═O)— K137 J001 T148 1124—CH₂— —C(═O)— K137 J001 T151 1125 —CH₂— —C(═O)— K137 J001 T152 1126—CH₂— —C(═O)— K137 J001 T164 1127 —CH₂— —C(═O)— K137 J001 T170 1128—CH₂— —C(═O)— K137 J001 T172 1129 —CH₂— —C(═O)— K137 J009 T148 1130—CH₂— —C(═O)— K137 J012 T148 1131 —CH₂— —C(═O)— K237 J001 T148 1132—CH₂— —C(═O)—NH— K001 J001 T148 1133 —CH₂— —C(═O)—NH— K002 J001 T1481134 —CH₂— —C(═O)—NH— K002 J012 T148 1135 —CH₂— —C(═O)—NH— K002 J063T148 1136 —CH₂— —C(═O)—NH— K003 J001 T148 1137 —CH₂— —C(═O)—NH— K003J012 T148 1138 —CH₂— —C(═O)—NH— K003 J065 T148 1139 —CH₂— —C(═O)—NH—K004 J001 T148 1140 —CH₂— —C(═O)—NH— K004 J012 T148 1141 —CH₂——C(═O)—NH— K004 J070 T148 1142 —CH₂— —C(═O)—NH— K005 J001 T148 1143—CH₂— —C(═O)—NH— K005 J012 T148 1144 —CH₂— —C(═O)—NH— K005 J075 T1481145 —CH₂— —C(═O)—NH— K007 J001 T129 1146 —CH₂— —C(═O)—NH— K007 J001T148 1147 —CH₂— —C(═O)—NH— K007 J001 T151 1148 —CH₂— —C(═O)—NH— K007J001 T152 1149 —CH₂— —C(═O)—NH— K007 J001 T164 1150 —CH₂— —C(═O)—NH—K007 J001 T169 1151 —CH₂— —C(═O)—NH— K007 J001 T170 1152 —CH₂——C(═O)—NH— K007 J012 T148 1153 —CH₂— —C(═O)—NH— K007 J081 T148 1154—CH₂— —C(═O)—NH— K008 J001 T148 1155 —CH₂— —C(═O)—NH— K008 J012 T1481156 —CH₂— —C(═O)—NH— K008 J085 T148 1157 —CH₂— —C(═O)—NH— K009 J001T148 1158 —CH₂— —C(═O)—NH— K009 J012 T148 1159 —CH₂— —C(═O)—NH— K009J043 T148 1160 —CH₂— —C(═O)—NH— K012 J001 T129 1161 —CH₂— —C(═O)—NH—K012 J001 T148 1162 —CH₂— —C(═O)—NH— K012 J001 T151 1163 —CH₂——C(═O)—NH— K012 J001 T152 1164 —CH₂— —C(═O)—NH— K012 J001 T164 1165—CH₂— —C(═O)—NH— K012 J001 T170 1166 —CH₂— —C(═O)—NH— K012 J012 T1481167 —CH₂— —C(═O)—NH— K012 J045 T148 1168 —CH₂— —C(═O)—NH— K218 J001T148 1169 —CH₂— —C(═O)—O— K001 J001 T148 1170 —CH₂— —C(═O)—O— K002 J001T148 1171 —CH₂— —C(═O)—O— K002 J001 T151 1172 —CH₂— —C(═O)—O— K193 J001T152 1173 —CH₂— —C(═O)—O— K227 J001 T169 1174 Single bond Single bondK001 J001 T148 1175 Single bond Single bond K001 J002 T148 1176 Singlebond Single bond K197 J001 T005 1177 Single bond Single bond K197 J001T148 1178 Single bond Single bond K197 J012 T148 1179 Single bond Singlebond K223 J001 T148 1180 Single bond Single bond K223 J002 T148 1181—(CH₂)₂— —NH— K078 J001 T148 1182 —(CH₂)₂— —NH— K078 J045 T148 1183—(CH₂)₂— —NH— K078 J045 T170 1184 —(CH₂)₂— —NH— K182 J001 T148 1185—(CH₂)₂— —NH— K372 J045 T148 1186 —(CH₂)₂— —NH— K392 J045 T170 1187—(CH₂)₂— —NH—C(═O)— K003 J044 T170 1188 —(CH₂)₂— —NH—C(═O)— K004 J007T148 1189 —(CH₂)₂— —NH—C(═O)— K004 J010 T148 1190 —(CH₂)₂— —NH—C(═O)—K004 J013 T148 1191 —(CH₂)₂— —NH—C(═O)— K004 J014 T148 1192 —(CH₂)₂——NH—C(═O)— K004 J044 T148 1193 —(CH₂)₂— —NH—C(═O)— K004 J044 T170 1194—(CH₂)₂— —NH—C(═O)— K006 J007 T148 1195 —(CH₂)₂— —NH—C(═O)— K006 J010T148 1196 —(CH₂)₂— —NH—C(═O)— K006 J013 T148 1197 —(CH₂)₂— —NH—C(═O)—K007 J007 T148 1198 —(CH₂)₂— —NH—C(═O)— K007 J010 T148 1199 —(CH₂)₂——NH—C(═O)— K007 J013 T148 1200 —(CH₂)₂— —NH—C(═O)— K007 J014 T148 1201—(CH₂)₂— —NH—C(═O)— K007 J039 T170 1202 —(CH₂)₂— —NH—C(═O)— K007 J044T148 1203 —(CH₂)₂— —NH—C(═O)— K007 J044 T169 1204 —(CH₂)₂— —NH—C(═O)—K007 J044 T170 1205 —(CH₂)₂— —NH—C(═O)— K007 J045 T151 1206 —(CH₂)₂——NH—C(═O)— K007 J045 T170 1207 —(CH₂)₂— —NH—C(═O)— K008 J007 T148 1208—(CH₂)₂— —NH—C(═O)— K008 J010 T148 1209 —(CH₂)₂— —NH—C(═O)— K008 J013T148 1210 —(CH₂)₂— —NH—C(═O)— K008 J014 T148 1211 —(CH₂)₂— —NH—C(═O)—K008 J039 T170 1212 —(CH₂)₂— —NH—C(═O)— K008 J044 T148 1213 —(CH₂)₂——NH—C(═O)— K008 J044 T169 1214 —(CH₂)₂— —NH—C(═O)— K008 J044 T170 1215—(CH₂)₂— —NH—C(═O)— K008 J045 T151 1216 —(CH₂)₂— —NH—C(═O)— K008 J045T169 1217 —(CH₂)₂— —NH—C(═O)— K008 J045 T170 1218 —(CH₂)₂— —NH—C(═O)—K009 J007 T148 1219 —(CH₂)₂— —NH—C(═O)— K009 J010 T148 1220 —(CH₂)₂——NH—C(═O)— K009 J013 T148 1221 —(CH₂)₂— —NH—C(═O)— K009 J014 T148 1222—(CH₂)₂— —NH—C(═O)— K009 J037 T170 1223 —(CH₂)₂— —NH—C(═O)— K009 J039T170 1224 —(CH₂)₂— —NH—C(═O)— K009 J043 T170 1225 —(CH₂)₂— —NH—C(═O)—K009 J044 T148 1226 —(CH₂)₂— —NH—C(═O)— K009 J044 T170 1227 —(CH₂)₂——NH—C(═O)— K009 J045 T152 1228 —(CH₂)₂— —NH—C(═O)— K009 J045 T170 1229—(CH₂)₂— —NH—C(═O)— K009 J047 T170 1230 —(CH₂)₂— —NH—C(═O)— K009 J145T148 1231 —(CH₂)₂— —NH—C(═O)— K009 J147 T148 1232 —(CH₂)₂— —NH—C(═O)—K010 J012 T148 1233 —(CH₂)₂— —NH—C(═O)— K010 J012 T164 1234 —(CH₂)₂——NH—C(═O)— K010 J013 T148 1235 —(CH₂)₂— —NH—C(═O)— K010 J013 T170 1236—(CH₂)₂— —NH—C(═O)— K010 J045 T148 1237 —(CH₂)₂— —NH—C(═O)— K010 J045T170 1238 —(CH₂)₂— —NH—C(═O)— K010 J045 T178 1239 —(CH₂)₂— —NH—C(═O)—K010 J045 T179 1240 —(CH₂)₂— —NH—C(═O)— K011 J044 T170 1241 —(CH₂)₂——NH—C(═O)— K023 J045 T170 1242 —(CH₂)₂— —NH—C(═O)— K033 J045 T170 1243—(CH₂)₂— —NH—C(═O)— K104 J045 T170 1244 —(CH₂)₂— —NH—C(═O)— K198 J007T148 1245 —(CH₂)₂— —NH—C(═O)— K198 J010 T148 1246 —(CH₂)₂— —NH—C(═O)—K198 J013 T148 1247 —(CH₂)₂— —NH—C(═O)— K198 J014 T148 1248 —(CH₂)₂——NH—C(═O)— K198 J039 T170 1249 —(CH₂)₂— —NH—C(═O)— K198 J044 T170 1250—(CH₂)₂— —NH—C(═O)— K198 J045 T170 1251 —(CH₂)₂— —NH—C(═O)— K199 J007T148 1252 —(CH₂)₂— —NH—C(═O)— K199 J010 T148 1253 —(CH₂)₂— —NH—C(═O)—K199 J013 T148 1254 —(CH₂)₂— —NH—C(═O)— K199 J014 T148 1255 —(CH₂)₂——NH—C(═O)— K199 J039 T170 1256 —(CH₂)₂— —NH—C(═O)— K199 J044 T170 1257—(CH₂)₂— —NH—C(═O)— K199 J045 T170 1258 —(CH₂)₂— —NH—C(═O)— K200 J001T170 1259 —(CH₂)₂— —NH—C(═O)— K200 J002 T170 1260 —(CH₂)₂— —NH—C(═O)—K200 J007 T148 1261 —(CH₂)₂— —NH—C(═O)— K200 J007 T170 1262 —(CH₂)₂——NH—C(═O)— K200 J008 T170 1263 —(CH₂)₂— —NH—C(═O)— K200 J009 T164 1264—(CH₂)₂— —NH—C(═O)— K200 J009 T170 1265 —(CH₂)₂— —NH—C(═O)— K200 J010T148 1266 —(CH₂)₂— —NH—C(═O)— K200 J010 T170 1267 —(CH₂)₂— —NH—C(═O)—K200 J011 T148 1268 —(CH₂)₂— —NH—C(═O)— K200 J011 T164 1269 —(CH₂)₂——NH—C(═O)— K200 J011 T170 1270 —(CH₂)₂— —NH—C(═O)— K200 J012 T164 1271—(CH₂)₂— —NH—C(═O)— K200 J012 T170 1272 —(CH₂)₂— —NH—C(═O)— K200 J013T148 1273 —(CH₂)₂— —NH—C(═O)— K200 J013 T170 1274 —(CH₂)₂— —NH—C(═O)—K200 J014 T148 1275 —(CH₂)₂— —NH—C(═O)— K200 J037 T148 1276 —(CH₂)₂——NH—C(═O)— K200 J037 T169 1277 —(CH₂)₂— —NH—C(═O)— K200 J037 T170 1278—(CH₂)₂— —NH—C(═O)— K200 J038 T170 1279 —(CH₂)₂— —NH—C(═O)— K200 J039T148 1280 —(CH₂)₂— —NH—C(═O)— K200 J039 T164 1281 —(CH₂)₂— —NH—C(═O)—K200 J039 T170 1282 —(CH₂)₂— —NH—C(═O)— K200 J043 T148 1283 —(CH₂)₂——NH—C(═O)— K200 J043 T169 1284 —(CH₂)₂— —NH—C(═O)— K200 J043 T170 1285—(CH₂)₂— —NH—C(═O)— K200 J044 T148 1286 —(CH₂)₂— —NH—C(═O)— K200 J044T170 1287 —(CH₂)₂— —NH—C(═O)— K200 J045 T164 1288 —(CH₂)₂— —NH—C(═O)—K200 J045 T170 1289 —(CH₂)₂— —NH—C(═O)— K200 J045 T171 1290 —(CH₂)₂——NH—C(═O)— K200 J045 T177 1291 —(CH₂)₂— —NH—C(═O)— K200 J045 T178 1292—(CH₂)₂— —NH—C(═O)— K200 J045 T179 1293 —(CH₂)₂— —NH—C(═O)— K200 J045T180 1294 —(CH₂)₂— —NH—C(═O)— K200 J047 T148 1295 —(CH₂)₂— —NH—C(═O)—K200 J047 T169 1296 —(CH₂)₂— —NH—C(═O)— K200 J047 T170 1297 —(CH₂)₂——NH—C(═O)— K200 J079 T148 1298 —(CH₂)₂— —NH—C(═O)— K200 J079 T169 1299—(CH₂)₂— —NH—C(═O)— K200 J079 T170 1300 —(CH₂)₂— —NH—C(═O)— K200 J080T148 1301 —(CH₂)₂— —NH—C(═O)— K200 J080 T169 1302 —(CH₂)₂— —NH—C(═O)—K200 J080 T170 1303 —(CH₂)₂— —NH—C(═O)— K200 J081 T148 1304 —(CH₂)₂——NH—C(═O)— K200 J081 T164 1305 —(CH₂)₂— —NH—C(═O)— K200 J081 T170 1306—(CH₂)₂— —NH—C(═O)— K200 J082 T148 1307 —(CH₂)₂— —NH—C(═O)— K200 J082T169 1308 —(CH₂)₂— —NH—C(═O)— K200 J082 T170 1309 —(CH₂)₂— —NH—C(═O)—K200 J090 T148 1310 —(CH₂)₂— —NH—C(═O)— K200 J090 T169 1311 —(CH₂)₂——NH—C(═O)— K200 J090 T170 1312 —(CH₂)₂— —NH—C(═O)— K200 J092 T148 1313—(CH₂)₂— —NH—C(═O)— K200 J092 T164 1314 —(CH₂)₂— —NH—C(═O)— K200 J092T170 1315 —(CH₂)₂— —NH—C(═O)— K200 J093 T148 1316 —(CH₂)₂— —NH—C(═O)—K200 J103 T148 1317 —(CH₂)₂— —NH—C(═O)— K200 J103 T164 1318 —(CH₂)₂——NH—C(═O)— K200 J103 T170 1319 —(CH₂)₂— —NH—C(═O)— K200 J104 T148 1320—(CH₂)₂— —NH—C(═O)— K200 J104 T164 1321 —(CH₂)₂— —NH—C(═O)— K200 J104T170 1322 —(CH₂)₂— —NH—C(═O)— K200 J105 T148 1323 —(CH₂)₂— —NH—C(═O)—K200 J105 T164 1324 —(CH₂)₂— —NH—C(═O)— K200 J105 T169 1325 —(CH₂)₂——NH—C(═O)— K200 J106 T148 1326 —(CH₂)₂— —NH—C(═O)— K200 J106 T164 1327—(CH₂)₂— —NH—C(═O)— K200 J106 T170 1328 —(CH₂)₂— —NH—C(═O)— K200 J107T148 1329 —(CH₂)₂— —NH—C(═O)— K200 J107 T164 1330 —(CH₂)₂— —NH—C(═O)—K200 J107 T170 1331 —(CH₂)₂— —NH—C(═O)— K200 J109 T170 1332 —(CH₂)₂——NH—C(═O)— K200 J118 T170 1333 —(CH₂)₂— —NH—C(═O)— K200 J138 T170 1334—(CH₂)₂— —NH—C(═O)— K200 J139 T170 1335 —(CH₂)₂— —NH—C(═O)— K200 J144T148 1336 —(CH₂)₂— —NH—C(═O)— K200 J144 T169 1337 —(CH₂)₂— —NH—C(═O)—K200 J144 T170 1338 —(CH₂)₂— —NH—C(═O)— K200 J145 T170 1339 —(CH₂)₂——NH—C(═O)— K200 J146 T148 1340 —(CH₂)₂— —NH—C(═O)— K200 J146 T164 1341—(CH₂)₂— —NH—C(═O)— K200 J105 T170 1342 —(CH₂)₂— —NH—C(═O)— K200 J147T148 1343 —(CH₂)₂— —NH—C(═O)— K200 J147 T170 1344 —(CH₂)₂— —NH—C(═O)—K200 J148 T148 1345 —(CH₂)₂— —NH—C(═O)— K200 J149 T148 1346 —(CH₂)₂——NH—C(═O)— K200 J149 T170 1347 —(CH₂)₂— —NH—C(═O)— K200 J150 T148 1348—(CH₂)₂— —NH—C(═O)— K200 J150 T170 1349 —(CH₂)₂— —NH—C(═O)— K200 J151T148 1350 —(CH₂)₂— —NH—C(═O)— K200 J151 T170 1351 —(CH₂)₂— —NH—C(═O)—K200 J152 T148 1352 —(CH₂)₂— —NH—C(═O)— K200 J153 T148 1353 —(CH₂)₂——NH—C(═O)— K200 J154 T148 1354 —(CH₂)₂— —NH—C(═O)— K200 J155 T148 1355—(CH₂)₂— —NH—C(═O)— K200 J156 T148 1356 —(CH₂)₂— —NH—C(═O)— K200 J157T148 1357 —(CH₂)₂— —NH—C(═O)— K200 J158 T148 1358 —(CH₂)₂— —NH—C(═O)—K200 J158 T170 1359 —(CH₂)₂— —NH—C(═O)— K200 J159 T148 1360 —(CH₂)₂——NH—C(═O)— K200 J159 T170 1361 —(CH₂)₂— —NH—C(═O)— K201 J007 T148 1362—(CH₂)₂— —NH—C(═O)— K201 J008 T148 1363 —(CH₂)₂— —NH—C(═O)— K201 J010T148 1364 —(CH₂)₂— —NH—C(═O)— K201 J012 T148 1365 —(CH₂)₂— —NH—C(═O)—K201 J013 T148 1366 —(CH₂)₂— —NH—C(═O)— K201 J014 T148 1367 —(CH₂)₂——NH—C(═O)— K201 J037 T170 1368 —(CH₂)₂— —NH—C(═O)— K201 J039 T170 1369—(CH₂)₂— —NH—C(═O)— K201 J043 T170 1370 —(CH₂)₂— —NH—C(═O)— K201 J044T148 1371 —(CH₂)₂— —NH—C(═O)— K201 J044 T170 1372 —(CH₂)₂— —NH—C(═O)—K201 J045 T148 1373 —(CH₂)₂— —NH—C(═O)— K201 J045 T152 1374 —(CH₂)₂——NH—C(═O)— K201 J045 T170 1375 —(CH₂)₂— —NH—C(═O)— K201 J047 T170 1376—(CH₂)₂— —NH—C(═O)— K201 J145 T148 1377 —(CH₂)₂— —NH—C(═O)— K201 J147T148 1378 —(CH₂)₂— —NH—C(═O)— K202 J007 T148 1379 —(CH₂)₂— —NH—C(═O)—K202 J008 T148 1380 —(CH₂)₂— —NH—C(═O)— K202 J010 T148 1381 —(CH₂)₂——NH—C(═O)— K202 J012 T148 1382 —(CH₂)₂— —NH—C(═O)— K202 J013 T148 1383—(CH₂)₂— —NH—C(═O)— K202 J014 T148 1384 —(CH₂)₂— —NH—C(═O)— K202 J039T170 1385 —(CH₂)₂— —NH—C(═O)— K202 J044 T148 1386 —(CH₂)₂— —NH—C(═O)—K202 J044 T164 1387 —(CH₂)₂— —NH—C(═O)— K202 J044 T170 1388 —(CH₂)₂——NH—C(═O)— K202 J045 T148 1389 —(CH₂)₂— —NH—C(═O)— K202 J045 T164 1390—(CH₂)₂— —NH—C(═O)— K203 J007 T148 1391 —(CH₂)₂— —NH—C(═O)— K203 J010T148 1392 —(CH₂)₂— —NH—C(═O)— K203 J013 T148 1393 —(CH₂)₂— —NH—C(═O)—K203 J014 T148 1394 —(CH₂)₂— —NH—C(═O)— K203 J039 T170 1395 —(CH₂)₂——NH—C(═O)— K203 J044 T148 1396 —(CH₂)₂— —NH—C(═O)— K203 J044 T164 1397—(CH₂)₂— —NH—C(═O)— K203 J044 T170 1398 —(CH₂)₂— —NH—C(═O)— K203 J045T164 1399 —(CH₂)₂— —NH—C(═O)— K203 J045 T170 1400 —(CH₂)₂— —NH—C(═O)—K204 J007 T148 1401 —(CH₂)₂— —NH—C(═O)— K204 J008 T148 1402 —(CH₂)₂——NH—C(═O)— K204 J009 T170 1403 —(CH₂)₂— —NH—C(═O)— K204 J010 T148 1404—(CH₂)₂— —NH—C(═O)— K204 J011 T170 1405 —(CH₂)₂— —NH—C(═O)— K204 J012T148 1406 —(CH₂)₂— —NH—C(═O)— K204 J013 T148 1407 —(CH₂)₂— —NH—C(═O)—K204 J037 T170 1408 —(CH₂)₂— —NH—C(═O)— K204 J039 T170 1409 —(CH₂)₂——NH—C(═O)— K204 J043 T170 1410 —(CH₂)₂— —NH—C(═O)— K204 J044 T148 1411—(CH₂)₂— —NH—C(═O)— K204 J044 T169 1412 —(CH₂)₂— —NH—C(═O)— K204 J044T170 1413 —(CH₂)₂— —NH—C(═O)— K204 J045 T148 1414 —(CH₂)₂— —NH—C(═O)—K204 J045 T169 1415 —(CH₂)₂— —NH—C(═O)— K204 J045 T170 1416 —(CH₂)₂——NH—C(═O)— K204 J047 T170 1417 —(CH₂)₂— —NH—C(═O)— K204 J079 T170 1418—(CH₂)₂— —NH—C(═O)— K204 J145 T148 1419 —(CH₂)₂— —NH—C(═O)— K204 J147T148 1420 —(CH₂)₂— —NH—C(═O)— K205 J007 T148 1421 —(CH₂)₂— —NH—C(═O)—K205 J008 T148 1422 —(CH₂)₂— —NH—C(═O)— K205 J010 T148 1423 —(CH₂)₂——NH—C(═O)— K205 J012 T148 1424 —(CH₂)₂— —NH—C(═O)— K205 J013 T148 1425—(CH₂)₂— —NH—C(═O)— K205 J014 T148 1426 —(CH₂)₂— —NH—C(═O)— K205 J044T170 1427 —(CH₂)₂— —NH—C(═O)— K205 J045 T170 1428 —(CH₂)₂— —NH—C(═O)—K206 J039 T170 1429 —(CH₂)₂— —NH—C(═O)— K206 J044 T170 1430 —(CH₂)₂——NH—C(═O)— K206 J045 T170 1431 —(CH₂)₂— —NH—C(═O)— K207 J044 T170 1432—(CH₂)₂— —NH—C(═O)— K208 J007 T148 1433 —(CH₂)₂— —NH—C(═O)— K208 J009T170 1434 —(CH₂)₂— —NH—C(═O)— K208 J010 T148 1435 —(CH₂)₂— —NH—C(═O)—K208 J011 T170 1436 —(CH₂)₂— —NH—C(═O)— K208 J013 T148 1437 —(CH₂)₂——NH—C(═O)— K208 J014 T148 1438 —(CH₂)₂— —NH—C(═O)— K208 J037 T170 1439—(CH₂)₂— —NH—C(═O)— K208 J039 T170 1440 —(CH₂)₂— —NH—C(═O)— K208 J043T170 1441 —(CH₂)₂— —NH—C(═O)— K208 J044 T148 1442 —(CH₂)₂— —NH—C(═O)—K208 J044 T169 1443 —(CH₂)₂— —NH—C(═O)— K208 J044 T170 1444 —(CH₂)₂——NH—C(═O)— K208 J045 T169 1445 —(CH₂)₂— —NH—C(═O)— K208 J045 T170 1446—(CH₂)₂— —NH—C(═O)— K208 J047 T170 1447 —(CH₂)₂— —NH—C(═O)— K208 J079T170 1448 —(CH₂)₂— —NH—C(═O)— K208 J145 T148 1449 —(CH₂)₂— —NH—C(═O)—K208 J147 T148 1450 —(CH₂)₂— —NH—C(═O)— K209 J007 T148 1451 —(CH₂)₂——NH—C(═O)— K209 J010 T148 1452 —(CH₂)₂— —NH—C(═O)— K209 J013 T148 1453—(CH₂)₂— —NH—C(═O)— K209 J014 T148 1454 —(CH₂)₂— —NH—C(═O)— K209 J044T170 1455 —(CH₂)₂— —NH—C(═O)— K210 J007 T148 1456 —(CH₂)₂— —NH—C(═O)—K210 J010 T148 1457 —(CH₂)₂— —NH—C(═O)— K210 J013 T148 1458 —(CH₂)₂——NH—C(═O)— K210 J014 T148 1459 —(CH₂)₂— —NH—C(═O)— K210 J044 T170 1460—(CH₂)₂— —NH—C(═O)— K213 J007 T148 1461 —(CH₂)₂— —NH—C(═O)— K213 J008T148 1462 —(CH₂)₂— —NH—C(═O)— K213 J010 T148 1463 —(CH₂)₂— —NH—C(═O)—K213 J012 T148 1464 —(CH₂)₂— —NH—C(═O)— K213 J013 T148 1465 —(CH₂)₂——NH—C(═O)— K213 J014 T148 1466 —(CH₂)₂— —NH—C(═O)— K213 J044 T170 1467—(CH₂)₂— —NH—C(═O)— K214 J007 T148 1468 —(CH₂)₂— —NH—C(═O)— K214 J008T148 1469 —(CH₂)₂— —NH—C(═O)— K214 J010 T148 1470 —(CH₂)₂— —NH—C(═O)—K214 J012 T148 1471 —(CH₂)₂— —NH—C(═O)— K214 J013 T148 1472 —(CH₂)₂——NH—C(═O)— K214 J014 T148 1473 —(CH₂)₂— —NH—C(═O)— K214 J044 T170 1474—(CH₂)₂— —NH—C(═O)— K215 J007 T148 1475 —(CH₂)₂— —NH—C(═O)— K215 J010T148 1476 —(CH₂)₂— —NH—C(═O)— K215 J013 T148 1477 —(CH₂)₂— —NH—C(═O)—K215 J014 T148 1478 —(CH₂)₂— —NH—C(═O)— K215 J044 T170 1479 —(CH₂)₂——NH—C(═O)— K216 J007 T148 1480 —(CH₂)₂— —NH—C(═O)— K216 J008 T148 1481—(CH₂)₂— —NH—C(═O)— K216 J010 T148 1482 —(CH₂)₂— —NH—C(═O)— K216 J012T148 1483 —(CH₂)₂— —NH—C(═O)— K216 J013 T148 1484 —(CH₂)₂— —NH—C(═O)—K216 J014 T148 1485 —(CH₂)₂— —NH—C(═O)— K216 J044 T170 1486 —(CH₂)₂——NH—C(═O)— K216 J045 T170 1487 —(CH₂)₂— —NH—C(═O)— K217 J007 T148 1488—(CH₂)₂— —NH—C(═O)— K217 J008 T148 1489 —(CH₂)₂— —NH—C(═O)— K217 J010T148 1490 —(CH₂)₂— —NH—C(═O)— K217 J012 T148 1491 —(CH₂)₂— —NH—C(═O)—K217 J013 T148 1492 —(CH₂)₂— —NH—C(═O)— K217 J014 T148 1493 —(CH₂)₂——NH—C(═O)— K217 J044 T170 1494 —(CH₂)₂— —NH—C(═O)— K217 J045 T170 1495—(CH₂)₂— —NH—C(═O)— K218 J007 T148 1496 —(CH₂)₂— —NH—C(═O)— K218 J008T148 1497 —(CH₂)₂— —NH—C(═O)— K218 J010 T148 1498 —(CH₂)₂— —NH—C(═O)—K218 J012 T148 1499 —(CH₂)₂— —NH—C(═O)— K218 J012 T164 1500 —(CH₂)₂——NH—C(═O)— K218 J013 T148 1501 —(CH₂)₂— —NH—C(═O)— K218 J013 T170 1502—(CH₂)₂— —NH—C(═O)— K218 J014 T148 1503 —(CH₂)₂— —NH—C(═O)— K218 J044T170 1504 —(CH₂)₂— —NH—C(═O)— K218 J045 T170 1505 —(CH₂)₂— —NH—C(═O)—K218 J045 T178 1506 —(CH₂)₂— —NH—C(═O)— K218 J045 T179 1507 —(CH₂)₂——NH—C(═O)— K222 J007 T148 1508 —(CH₂)₂— —NH—C(═O)— K222 J010 T148 1509—(CH₂)₂— —NH—C(═O)— K222 J013 T148 1510 —(CH₂)₂— —NH—C(═O)— K222 J014T148 1511 —(CH₂)₂— —NH—C(═O)— K240 J045 T148 1512 —(CH₂)₂— —NH—C(═O)—K242 J045 T169 1513 —(CH₂)₂— —NH—C(═O)— K242 J045 T170 1514 —(CH₂)₂——NH—C(═O)— K243 J045 T170 1515 —(CH₂)₂— —NH—C(═O)— K244 J045 T169 1516—(CH₂)₂— —NH—C(═O)— K244 J045 T170 1517 —(CH₂)₂— —NH—C(═O)— K245 J045T170 1518 —(CH₂)₂— —NH—C(═O)— K246 J045 T170 1519 —(CH₂)₂— —NH—C(═O)—K247 J012 T148 1520 —(CH₂)₂— —NH—C(═O)— K247 J045 T148 1521 —(CH₂)₂——NH—C(═O)— K247 J045 T170 1522 —(CH₂)₂— —NH—C(═O)— K248 J045 T148 1523—(CH₂)₂— —NH—C(═O)— K248 J045 T170 1524 —(CH₂)₂— —NH—C(═O)— K249 J007T148 1525 —(CH₂)₂— —NH—C(═O)— K249 J008 T148 1526 —(CH₂)₂— —NH—C(═O)—K249 J010 T148 1527 —(CH₂)₂— —NH—C(═O)— K249 J013 T148 1528 —(CH₂)₂——NH—C(═O)— K249 J014 T148 1529 —(CH₂)₂— —NH—C(═O)— K249 J045 T170 1530—(CH₂)₂— —NH—C(═O)— K250 J045 T148 1531 —(CH₂)₂— —NH—C(═O)— K250 J045T170 1532 —(CH₂)₂— —NH—C(═O)— K251 J045 T170 1533 —(CH₂)₂— —NH—C(═O)—K252 J045 T148 1534 —(CH₂)₂— —NH—C(═O)— K252 J045 T170 1535 —(CH₂)₂——NH—C(═O)— K253 J045 T148 1536 —(CH₂)₂— —NH—C(═O)— K253 J045 T170 1537—(CH₂)₂— —NH—C(═O)— K254 J007 T148 1538 —(CH₂)₂— —NH—C(═O)— K254 J008T148 1539 —(CH₂)₂— —NH—C(═O)— K254 J010 T148 1540 —(CH₂)₂— —NH—C(═O)—K254 J012 T148 1541 —(CH₂)₂— —NH—C(═O)— K254 J013 T148 1542 —(CH₂)₂——NH—C(═O)— K254 J014 T148 1543 —(CH₂)₂— —NH—C(═O)— K254 J044 T170 1544—(CH₂)₂— —NH—C(═O)— K254 J045 T169 1545 —(CH₂)₂— —NH—C(═O)— K254 J045T170 1546 —(CH₂)₂— —NH—C(═O)— K255 J012 T148 1547 —(CH₂)₂— —NH—C(═O)—K255 J045 T169 1548 —(CH₂)₂— —NH—C(═O)— K255 J045 T170 1549 —(CH₂)₂——NH—C(═O)— K256 J012 T148 1550 —(CH₂)₂— —NH—C(═O)— K256 J039 T170 1551—(CH₂)₂— —NH—C(═O)— K256 J044 T170 1552 —(CH₂)₂— —NH—C(═O)— K256 J045T169 1553 —(CH₂)₂— —NH—C(═O)— K256 J045 T170 1554 —(CH₂)₂— —NH—C(═O)—K257 J012 T148 1555 —(CH₂)₂— —NH—C(═O)— K257 J039 T170 1556 —(CH₂)₂——NH—C(═O)— K257 J044 T170 1557 —(CH₂)₂— —NH—C(═O)— K257 J045 T169 1558—(CH₂)₂— —NH—C(═O)— K257 J045 T170 1559 —(CH₂)₂— —NH—C(═O)— K258 J012T148 1560 —(CH₂)₂— —NH—C(═O)— K258 J045 T169 1561 —(CH₂)₂— —NH—C(═O)—K258 J045 T170 1562 —(CH₂)₂— —NH—C(═O)— K259 J012 T148 1563 —(CH₂)₂——NH—C(═O)— K259 J039 T170 1564 —(CH₂)₂— —NH—C(═O)— K259 J044 T170 1565—(CH₂)₂— —NH—C(═O)— K259 J045 T169 1566 —(CH₂)₂— —NH—C(═O)— K259 J045T170 1567 —(CH₂)₂— —NH—C(═O)— K260 J012 T148 1568 —(CH₂)₂— —NH—C(═O)—K260 J045 T169 1569 —(CH₂)₂— —NH—C(═O)— K260 J045 T170 1570 —(CH₂)₂——NH—C(═O)— K261 J012 T148 1571 —(CH₂)₂— —NH—C(═O)— K261 J045 T169 1572—(CH₂)₂— —NH—C(═O)— K261 J045 T170 1573 —(CH₂)₂— —NH—C(═O)— K262 J007T148 1574 —(CH₂)₂— —NH—C(═O)— K262 J008 T148 1575 —(CH₂)₂— —NH—C(═O)—K262 J010 T148 1576 —(CH₂)₂— —NH—C(═O)— K262 J012 T148 1577 —(CH₂)₂——NH—C(═O)— K262 J013 T148 1578 —(CH₂)₂— —NH—C(═O)— K262 J014 T148 1579—(CH₂)₂— —NH—C(═O)— K262 J044 T148 1580 —(CH₂)₂— —NH—C(═O)— K262 J044T170 1581 —(CH₂)₂— —NH—C(═O)— K262 J044 T178 1582 —(CH₂)₂— —NH—C(═O)—K262 J045 T148 1583 —(CH₂)₂— —NH—C(═O)— K262 J045 T169 1584 —(CH₂)₂——NH—C(═O)— K262 J045 T170 1585 —(CH₂)₂— —NH—C(═O)— K262 J045 T178 1586—(CH₂)₂— —NH—C(═O)— K263 J007 T148 1587 —(CH₂)₂— —NH—C(═O)— K263 J008T148 1588 —(CH₂)₂— —NH—C(═O)— K263 J010 T148 1589 —(CH₂)₂— —NH—C(═O)—K263 J012 T148 1590 —(CH₂)₂— —NH—C(═O)— K263 J012 T164 1591 —(CH₂)₂——NH—C(═O)— K263 J013 T148 1592 —(CH₂)₂— —NH—C(═O)— K263 J013 T170 1593—(CH₂)₂— —NH—C(═O)— K263 J014 T148 1594 —(CH₂)₂— —NH—C(═O)— K263 J039T170 1595 —(CH₂)₂— —NH—C(═O)— K263 J044 T148 1596 —(CH₂)₂— —NH—C(═O)—K263 J044 T170 1597 —(CH₂)₂— —NH—C(═O)— K263 J044 T179 1598 —(CH₂)₂——NH—C(═O)— K263 J045 T148 1599 —(CH₂)₂— —NH—C(═O)— K263 J045 T169 1600—(CH₂)₂— —NH—C(═O)— K263 J045 T170 1601 —(CH₂)₂— —NH—C(═O)— K263 J045T178 1602 —(CH₂)₂— —NH—C(═O)— K263 J045 T179 1603 —(CH₂)₂— —NH—C(═O)—K264 J012 T148 1604 —(CH₂)₂— —NH—C(═O)— K264 J045 T169 1605 —(CH₂)₂——NH—C(═O)— K264 J045 T170 1606 —(CH₂)₂— —NH—C(═O)— K265 J012 T148 1607—(CH₂)₂— —NH—C(═O)— K265 J044 T148 1608 —(CH₂)₂— —NH—C(═O)— K265 J044T180 1609 —(CH₂)₂— —NH—C(═O)— K265 J045 T148 1610 —(CH₂)₂— —NH—C(═O)—K265 J045 T169 1611 —(CH₂)₂— —NH—C(═O)— K265 J045 T170 1612 —(CH₂)₂——NH—C(═O)— K265 J045 T180 1613 —(CH₂)₂— —NH—C(═O)— K266 J012 T148 1614—(CH₂)₂— —NH—C(═O)— K266 J045 T169 1615 —(CH₂)₂— —NH—C(═O)— K266 J045T170 1616 —(CH₂)₂— —NH—C(═O)— K267 J012 T148 1617 —(CH₂)₂— —NH—C(═O)—K267 J045 T169 1618 —(CH₂)₂— —NH—C(═O)— K267 J045 T170 1619 —(CH₂)₂——NH—C(═O)— K268 J012 T148 1620 —(CH₂)₂— —NH—C(═O)— K268 J045 T170 1621—(CH₂)₂— —NH—C(═O)— K269 J012 T148 1622 —(CH₂)₂— —NH—C(═O)— K269 J045T170 1623 —(CH₂)₂— —NH—C(═O)— K210 J012 T148 1624 —(CH₂)₂— —NH—C(═O)—K270 J045 T170 1625 —(CH₂)₂— —NH—C(═O)— K271 J012 T148 1626 —(CH₂)₂——NH—C(═O)— K271 J045 T169 1627 —(CH₂)₂— —NH—C(═O)— K271 J045 T170 1628—(CH₂)₂— —NH—C(═O)— K272 J012 T148 1629 —(CH₂)₂— —NH—C(═O)— K272 J045T169 1630 —(CH₂)₂— —NH—C(═O)— K272 J045 T170 1631 —(CH₂)₂— —NH—C(═O)—K273 J012 T148 1632 —(CH₂)₂— —NH—C(═O)— K273 J045 T170 1633 —(CH₂)₂——NH—C(═O)— K274 J012 T148 1634 —(CH₂)₂— —NH—C(═O)— K274 J045 T170 1635—(CH₂)₂— —NH—C(═O)— K275 J007 T148 1636 —(CH₂)₂— —NH—C(═O)— K275 J008T148 1637 —(CH₂)₂— —NH—C(═O)— K275 J010 T148 1638 —(CH₂)₂— —NH—C(═O)—K275 J012 T148 1639 —(CH₂)₂— —NH—C(═O)— K275 J013 T148 1640 —(CH₂)₂——NH—C(═O)— K275 J014 T148 1641 —(CH₂)₂— —NH—C(═O)— K275 J044 T170 1642—(CH₂)₂— —NH—C(═O)— K275 J045 T169 1643 —(CH₂)₂— —NH—C(═O)— K275 J045T170 1644 —(CH₂)₂— —NH—C(═O)— K276 J007 T148 1645 —(CH₂)₂— —NH—C(═O)—K276 J008 T148 1646 —(CH₂)₂— —NH—C(═O)— K276 J010 T148 1647 —(CH₂)₂——NH—C(═O)— K276 J012 T148 1648 —(CH₂)₂— —NH—C(═O)— K276 J012 T164 1649—(CH₂)₂— —NH—C(═O)— K276 J013 T148 1650 —(CH₂)₂— —NH—C(═O)— K276 J013T170 1651 —(CH₂)₂— —NH—C(═O)— K276 J014 T148 1652 —(CH₂)₂— —NH—C(═O)—K276 J044 T170 1653 —(CH₂)₂— —NH—C(═O)— K276 J045 T169 1654 —(CH₂)₂——NH—C(═O)— K276 J045 T170 1655 —(CH₂)₂— —NH—C(═O)— K276 J045 T178 1656—(CH₂)₂— —NH—C(═O)— K276 J045 T179 1657 —(CH₂)₂— —NH—C(═O)— K277 J045T170 1658 —(CH₂)₂— —NH—C(═O)— K278 J045 T170 1659 —(CH₂)₂— —NH—C(═O)—K279 J045 T170 1660 —(CH₂)₂— —NH—C(═O)— K280 J012 T148 1661 —(CH₂)₂——NH—C(═O)— K280 J045 T170 1662 —(CH₂)₂— —NH—C(═O)— K281 J045 T170 1663—(CH₂)₂— —NH—C(═O)— K282 J045 T170 1664 —(CH₂)₂— —NH—C(═O)— K283 J045T170 1665 —(CH₂)₂— —NH—C(═O)— K284 J045 T170 1666 —(CH₂)₂— —NH—C(═O)—K285 J045 T170 1667 —(CH₂)₂— —NH—C(═O)— K286 J045 T170 1668 —(CH₂)₂——NH—C(═O)— K287 J045 T170 1669 —(CH₂)₂— —NH—C(═O)— K288 J045 T170 1670—(CH₂)₂— —NH—C(═O)— K289 J007 T148 1671 —(CH₂)₂— —NH—C(═O)— K289 J008T148 1672 —(CH₂)₂— —NH—C(═O)— K289 J010 T148 1673 —(CH₂)₂— —NH—C(═O)—K289 J012 T148 1674 —(CH₂)₂— —NH—C(═O)— K289 J013 T148 1675 —(CH₂)₂——NH—C(═O)— K289 J014 T148 1676 —(CH₂)₂— —NH—C(═O)— K289 J044 T169 1677—(CH₂)₂— —NH—C(═O)— K289 J044 T170 1678 —(CH₂)₂— —NH—C(═O)— K289 J045T169 1679 —(CH₂)₂— —NH—C(═O)— K289 J045 T170 1680 —(CH₂)₂— —NH—C(═O)—K290 J045 T170 1681 —(CH₂)₂— —NH—C(═O)— K291 J045 T170 1682 —(CH₂)₂——NH—C(═O)— K292 J045 T148 1683 —(CH₂)₂— —NH—C(═O)— K292 J045 T170 1684—(CH₂)₂— —NH—C(═O)— K293 J007 T148 1685 —(CH₂)₂— —NH—C(═O)— K293 J008T148 1686 —(CH₂)₂— —NH—C(═O)— K293 J010 T148 1687 —(CH₂)₂— —NH—C(═O)—K293 J012 T148 1688 —(CH₂)₂— —NH—C(═O)— K293 J013 T148 1689 —(CH₂)₂——NH—C(═O)— K293 J014 T148 1690 —(CH₂)₂— —NH—C(═O)— K293 J044 T170 1691—(CH₂)₂— —NH—C(═O)— K293 J045 T148 1692 —(CH₂)₂— —NH—C(═O)— K293 J045T169 1693 —(CH₂)₂— —NH—C(═O)— K293 J045 T170 1694 —(CH₂)₂— —NH—C(═O)—K294 J045 T170 1695 —(CH₂)₂— —NH—C(═O)— K295 J045 T170 1696 —(CH₂)₂——NH—C(═O)— K295/K296 J045 T148 1697 —(CH₂)₂— —NH—C(═O)— K296 J045 T1701698 —(CH₂)₂— —NH—C(═O)— K297 J045 T170 1699 —(CH₂)₂— —NH—C(═O)— K298J045 T148 1700 —(CH₂)₂— —NH—C(═O)— K298 J045 T170 1701 —(CH₂)₂——NH—C(═O)— K299 J045 T170 1702 —(CH₂)₂— —NH—C(═O)— K300 J045 T170 1703—(CH₂)₂— —NH—C(═O)— K301 J044 T170 1704 —(CH₂)₂— —NH—C(═O)— K301 J045T169 1705 —(CH₂)₂— —NH—C(═O)— K301 J045 T170 1706 —(CH₂)₂— —NH—C(═O)—K302 J012 T148 1707 —(CH₂)₂— —NH—C(═O)— K302 J044 T170 1708 —(CH₂)₂——NH—C(═O)— K302 J045 T170 1709 —(CH₂)₂— —NH—C(═O)— K303 J007 T148 1710—(CH₂)₂— —NH—C(═O)— K303 J008 T148 1711 —(CH₂)₂— —NH—C(═O)— K303 J010T148 1712 —(CH₂)₂— —NH—C(═O)— K303 J013 T148 1713 —(CH₂)₂— —NH—C(═O)—K303 J014 T148 1714 —(CH₂)₂— —NH—C(═O)— K303 J044 T170 1715 —(CH₂)₂——NH—C(═O)— K303 J045 T148 1716 —(CH₂)₂— —NH—C(═O)— K303 J045 T169 1717—(CH₂)₂— —NH—C(═O)— K303 J045 T170 1718 —(CH₂)₂— —NH—C(═O)— K304 J012T148 1719 —(CH₂)₂— —NH—C(═O)— K304 J045 T148 1720 —(CH₂)₂— —NH—C(═O)—K304 J045 T170 1721 —(CH₂)₂— —NH—C(═O)— K305 J045 T148 1722 —(CH₂)₂——NH—C(═O)— K305 J045 T170 1723 —(CH₂)₂— —NH—C(═O)— K306 J044 T170 1724—(CH₂)₂— —NH—C(═O)— K306 J045 T170 1725 —(CH₂)₂— —NH—C(═O)— K307 J045T170 1726 —(CH₂)₂— —NH—C(═O)— K308 J007 T148 1727 —(CH₂)₂— —NH—C(═O)—K308 J008 T148 1728 —(CH₂)₂— —NH—C(═O)— K308 J010 T148 1729 —(CH₂)₂——NH—C(═O)— K308 J012 T148 1730 —(CH₂)₂— —NH—C(═O)— K308 J013 T148 1731—(CH₂)₂— —NH—C(═O)— K308 J014 T148 1732 —(CH₂)₂— —NH—C(═O)— K308 J045T170 1733 —(CH₂)₂— —NH—C(═O)— K309 J045 T170 1734 —(CH₂)₂— —NH—C(═O)—K310 J045 T170 1735 —(CH₂)₂— —NH—C(═O)— K311 J045 T170 1736 —(CH₂)₂——NH—C(═O)— K312 J012 T148 1737 —(CH₂)₂— —NH—C(═O)— K312 J045 T170 1738—(CH₂)₂— —NH—C(═O)— K313 J012 T148 1739 —(CH₂)₂— —NH—C(═O)— K313 J045T148 1740 —(CH₂)₂— —NH—C(═O)— K313 J045 T170 1741 —(CH₂)₂— —NH—C(═O)—K314 J007 T148 1742 —(CH₂)₂— —NH—C(═O)— K314 J008 T148 1743 —(CH₂)₂——NH—C(═O)— K314 J010 T148 1744 —(CH₂)₂— —NH—C(═O)— K314 J012 T148 1745—(CH₂)₂— —NH—C(═O)— K314 J013 T148 1746 —(CH₂)₂— —NH—C(═O)— K314 J014T148 1747 —(CH₂)₂— —NH—C(═O)— K314 J044 T170 1748 —(CH₂)₂— —NH—C(═O)—K314 J045 T148 1749 —(CH₂)₂— —NH—C(═O)— K314 J045 T169 1750 —(CH₂)₂——NH—C(═O)— K314 J045 T170 1751 —(CH₂)₂— —NH—C(═O)— K315 J045 T148 1752—(CH₂)₂— —NH—C(═O)— K315 J045 T170 1753 —(CH₂)₂— —NH—C(═O)— K316 J045T148 1754 —(CH₂)₂— —NH—C(═O)— K316 J045 T170 1755 —(CH₂)₂— —NH—C(═O)—K317 J012 T148 1756 —(CH₂)₂— —NH—C(═O)— K317 J045 T170 1757 —(CH₂)₂——NH—C(═O)— K318 J045 T170 1758 —(CH₂)₂— —NH—C(═O)— K319 J045 T148 1759—(CH₂)₂— —NH—C(═O)— K319 J045 T170 1760 —(CH₂)₂— —NH—C(═O)— K320 J045T170 1761 —(CH₂)₂— —NH—C(═O)— K321 J045 T170 1762 —(CH₂)₂— —NH—C(═O)—K322 J045 T170 1763 —(CH₂)₂— —NH—C(═O)— K323 J007 T148 1764 —(CH₂)₂——NH—C(═O)— K323 J008 T148 1765 —(CH₂)₂— —NH—C(═O)— K323 J010 T148 1766—(CH₂)₂— —NH—C(═O)— K323 J013 T148 1767 —(CH₂)₂— —NH—C(═O)— K323 J014T148 1768 —(CH₂)₂— —NH—C(═O)— K323 J045 T169 1769 —(CH₂)₂— —NH—C(═O)—K323 J045 T170 1770 —(CH₂)₂— —NH—C(═O)— K326 J045 T170 1771 —(CH₂)₂——NH—C(═O)— K332 J012 T148 1772 —(CH₂)₂— —NH—C(═O)— K332 J012 T164 1773—(CH₂)₂— —NH—C(═O)— K332 J013 T148 1774 —(CH₂)₂— —NH—C(═O)— K332 J013T170 1775 —(CH₂)₂— —NH—C(═O)— K332 J045 T170 1776 —(CH₂)₂— —NH—C(═O)—K332 J045 T178 1777 —(CH₂)₂— —NH—C(═O)— K332 J045 T179 1778 —(CH₂)₂——NH—C(═O)— K333 J012 T148 1779 —(CH₂)₂— —NH—C(═O)— K333 J012 T164 1780—(CH₂)₂— —NH—C(═O)— K333 J013 T148 1781 —(CH₂)₂— —NH—C(═O)— K333 J013T170 1782 —(CH₂)₂— —NH—C(═O)— K333 J045 T170 1783 —(CH₂)₂— —NH—C(═O)—K333 J045 T178 1784 —(CH₂)₂— —NH—C(═O)— K333 J045 T179 1785 —(CH₂)₂——NH—C(═O)— K335 J012 T148 1786 —(CH₂)₂— —NH—C(═O)— K335 J012 T164 1787—(CH₂)₂— —NH—C(═O)— K335 J013 T148 1788 —(CH₂)₂— —NH—C(═O)— K335 J013T170 1789 —(CH₂)₂— —NH—C(═O)— K335 J045 T170 1790 —(CH₂)₂— —NH—C(═O)—K335 J045 T178 1791 —(CH₂)₂— —NH—C(═O)— K335 J045 T179 1792 —(CH₂)₂——NH—C(═O)— K336 J012 T148 1793 —(CH₂)₂— —NH—C(═O)— K336 J012 T164 1794—(CH₂)₂— —NH—C(═O)— K336 J013 T148 1795 —(CH₂)₂— —NH—C(═O)— K336 J013T170 1796 —(CH₂)₂— —NH—C(═O)— K336 J045 T170 1797 —(CH₂)₂— —NH—C(═O)—K336 J045 T178 1798 —(CH₂)₂— —NH—C(═O)— K336 J045 T179 1799 —(CH₂)₂——NH—C(═O)— K340 J045 T170 1800 —(CH₂)₂— —NH—C(═O)— K343 J045 T170 1801—(CH₂)₂— —NH—C(═O)— K345 J045 T169 1802 —(CH₂)₂— —NH—C(═O)— K346 J045T169 1803 —(CH₂)₂— —NH—C(═O)— K346 J045 T170 1804 —(CH₂)₂— —NH—C(═O)—K355 J045 T148 1805 —(CH₂)₂— —NH—C(═O)— K356 J045 T148 1806 —(CH₂)₂——NH—C(═O)— K357 J045 T148 1807 —(CH₂)₂— —NH—C(═O)— K357 J045 T170 1808—(CH₂)₂— —NH—C(═O)— K358 J045 T148 1809 —(CH₂)₂— —NH—C(═O)— K358 J045T170 1810 —(CH₂)₂— —NH—C(═O)— K359 J012 T170 1811 —(CH₂)₂— —NH—C(═O)—K359 J045 T170 1812 —(CH₂)₂— —NH—C(═O)— K360 J012 T170 1813 —(CH₂)₂——NH—C(═O)— K360 J045 T170 1814 —(CH₂)₂— —NH—C(═O)— K361 J012 T170 1815—(CH₂)₂— —NH—C(═O)— K361 J045 T170 1816 —(CH₂)₂— —NH—C(═O)— K362 J012T170 1817 —(CH₂)₂— —NH—C(═O)— K362 J045 T170 1818 —(CH₂)₂— —NH—C(═O)—K363 J012 T170 1819 —(CH₂)₂— —NH—C(═O)— K363 J045 T170 1820 —(CH₂)₂——NH—C(═O)— K364 J012 T170 1821 —(CH₂)₂— —NH—C(═O)— K364 J045 T170 1822—(CH₂)₂— —NH—C(═O)— K365 J012 T170 1823 —(CH₂)₂— —NH—C(═O)— K365 J045T148 1824 —(CH₂)₂— —NH—C(═O)— K365 J045 T170 1825 —(CH₂)₂— —NH—C(═O)—K366 J012 T170 1826 —(CH₂)₂— —NH—C(═O)— K366 J045 T170 1827 —(CH₂)₂——NH—C(═O)— K367 J012 T170 1828 —(CH₂)₂— —NH—C(═O)— K367 J045 T148 1829—(CH₂)₂— —NH—C(═O)— K367 J045 T170 1830 —(CH₂)₂— —NH—C(═O)— K368 J012T170 1831 —(CH₂)₂— —NH—C(═O)— K368 J045 T170 1832 —(CH₂)₂— —NH—C(═O)—K369 J012 T170 1833 —(CH₂)₂— —NH—C(═O)— K369 J045 T148 1834 —(CH₂)₂——NH—C(═O)— K369 J045 T170 1835 —(CH₂)₂— —NH—C(═O)— K370 J012 T170 1836—(CH₂)₂— —NH—C(═O)— K370 J045 T170 1837 —(CH₂)₂— —NH—C(═O)— K371 J012T170 1838 —(CH₂)₂— —NH—C(═O)— K371 J045 T170 1839 —(CH₂)₂— —NH—C(═O)—K372 J012 T170 1840 —(CH₂)₂— —NH—C(═O)— K372 J045 T170 1841 —(CH₂)₂——NH—C(═O)— K373 J012 T170 1842 —(CH₂)₂— —NH—C(═O)— K373 J045 T170 1843—(CH₂)₂— —NH—C(═O)— K374 J012 T148 1844 —(CH₂)₂— —NH—C(═O)— K374 J012T170 1845 —(CH₂)₂— —NH—C(═O)— K374 J045 T170 1846 —(CH₂)₂— —NH—C(═O)—K375 J012 T148 1847 —(CH₂)₂— —NH—C(═O)— K375 J012 T170 1848 —(CH₂)₂——NH—C(═O)— K375 J045 T170 1849 —(CH₂)₂— —NH—C(═O)— K376 J012 T148 1850—(CH₂)₂— —NH—C(═O)— K376 J012 T170 1851 —(CH₂)₂— —NH—C(═O)— K376 J045T170 1852 —(CH₂)₂— —NH—C(═O)— K377 J012 T148 1853 —(CH₂)₂— —NH—C(═O)—K377 J012 T170 1854 —(CH₂)₂— —NH—C(═O)— K377 J045 T170 1855 —(CH₂)₂——NH—C(═O)— K378 J012 T148 1856 —(CH₂)₂— —NH—C(═O)— K378 J012 T170 1857—(CH₂)₂— —NH—C(═O)— K378 J039 T170 1858 —(CH₂)₂— —NH—C(═O)— K378 J044T170 1859 —(CH₂)₂— —NH—C(═O)— K378 J045 T169 1860 —(CH₂)₂— —NH—C(═O)—K378 J045 T170 1861 —(CH₂)₂— —NH—C(═O)— K379 J012 T148 1862 —(CH₂)₂——NH—C(═O)— K379 J012 T170 1863 —(CH₂)₂— —NH—C(═O)— K379 J045 T169 1864—(CH₂)₂— —NH—C(═O)— K379 J045 T170 1865 —(CH₂)₂— —NH—C(═O)— K380 J012T148 1866 —(CH₂)₂— —NH—C(═O)— K380 J012 T170 1867 —(CH₂)₂— —NH—C(═O)—K380 J045 T170 1868 —(CH₂)₂— —NH—C(═O)— K381 J012 T148 1869 —(CH₂)₂——NH—C(═O)— K381 J012 T170 1870 —(CH₂)₂— —NH—C(═O)— K381 J045 T169 1871—(CH₂)₂— —NH—C(═O)— K381 J045 T170 1872 —(CH₂)₂— —NH—C(═O)— K382 J007T148 1873 —(CH₂)₂— —NH—C(═O)— K382 J008 T148 1874 —(CH₂)₂— —NH—C(═O)—K382 J010 T148 1875 —(CH₂)₂— —NH—C(═O)— K382 J012 T148 1876 —(CH₂)₂——NH—C(═O)— K382 J012 T170 1877 —(CH₂)₂— —NH—C(═O)— K382 J013 T148 1878—(CH₂)₂— —NH—C(═O)— K382 J014 T148 1879 —(CH₂)₂— —NH—C(═O)— K382 J039T170 1880 —(CH₂)₂— —NH—C(═O)— K382 J044 T170 1881 —(CH₂)₂— —NH—C(═O)—K382 J045 T169 1882 —(CH₂)₂— —NH—C(═O)— K382 J045 T170 1883 —(CH₂)₂——NH—C(═O)— K383 J012 T170 1884 —(CH₂)₂— —NH—C(═O)— K383 J045 T170 1885—(CH₂)₂— —NH—C(═O)— K384 J012 T148 1886 —(CH₂)₂— —NH—C(═O)— K384 J012T170 1887 —(CH₂)₂— —NH—C(═O)— K384 J039 T170 1888 —(CH₂)₂— —NH—C(═O)—K384 J044 T170 1889 —(CH₂)₂— —NH—C(═O)— K384 J045 T169 1890 —(CH₂)₂——NH—C(═O)— K384 J045 T170 1891 —(CH₂)₂— —NH—C(═O)— K385 J012 T148 1892—(CH₂)₂— —NH—C(═O)— K385 J012 T170 1893 —(CH₂)₂— —NH—C(═O)— K385 J045T169 1894 —(CH₂)₂— —NH—C(═O)— K385 J045 T170 1895 —(CH₂)₂— —NH—C(═O)—K386 J012 T148 1896 —(CH₂)₂— —NH—C(═O)— K386 J039 T170 1897 —(CH₂)₂——NH—C(═O)— K386 J044 T170 1898 —(CH₂)₂— —NH—C(═O)— K386 J045 T170 1899—(CH₂)₂— —NH—C(═O)— K387 J012 T148 1900 —(CH₂)₂— —NH—C(═O)— K387 J045T170 1901 —(CH₂)₂— —NH—C(═O)— K388 J012 T148 1902 —(CH₂)₂— —NH—C(═O)—K388 J039 T170 1903 —(CH₂)₂— —NH—C(═O)— K388 J044 T170 1904 —(CH₂)₂——NH—C(═O)— K388 J045 T170 1905 —(CH₂)₂— —NH—C(═O)— K389 J012 T148 1906—(CH₂)₂— —NH—C(═O)— K389 J045 T170 1907 —(CH₂)₂— —NH—C(═O)— K390 J012T148 1908 —(CH₂)₂— —NH—C(═O)— K390 J045 T170 1909 —(CH₂)₂— —NH—C(═O)—K391 J012 T148 1910 —(CH₂)₂— —NH—C(═O)— K391 J045 T170 1911 —(CH₂)₂——NH—C(═O)— K392 J012 T148 1912 —(CH₂)₂— —NH—C(═O)— K392 J045 T170 1913—(CH₂)₂— —NH—C(═O)— K393 J012 T148 1914 —(CH₂)₂— —NH—C(═O)— K393 J045T170 1915 —(CH₂)₂— —NH—C(═O)— K394 J012 T148 1916 —(CH₂)₂— —NH—C(═O)—K394 J045 T170 1917 —(CH₂)₂— —NH—C(═O)— K398 J012 T148 1918 —(CH₂)₂——NH—C(═O)— K399 J010 T148 1919 —(CH₂)₂— —NH—C(═O)— K399 J010 T170 1920—(CH₂)₂— —NH—C(═O)— K399 J012 T148 1921 —(CH₂)₂— —NH—C(═O)— K399 J013T148 1922 —(CH₂)₂— —NH—C(═O)— K399 J013 T170 1923 —(CH₂)₂— —NH—C(═O)—K399 J044 T170 1924 —(CH₂)₂— —NH—C(═O)— K399 J045 T170 1925 —(CH₂)₂——NH—C(═O)— K399 J146 T148 1926 —(CH₂)₂— —NH—C(═O)— K399 J147 T148 1927—(CH₂)₂— —NH—C(═O)— K399 J150 T148 1928 —(CH₂)₂— —NH—C(═O)— K399 J150T170 1929 —(CH₂)₂— —NH—C(═O)— K399 J151 T148 1930 —(CH₂)₂— —NH—C(═O)—K399 J159 T148 1931 —(CH₂)₂— —NH—C(═O)— K399 J159 T170 1932 —(CH₂)₂——NH—C(═O)— K400 J012 T148 1933 —(CH₂)₂— —NH—C(═O)— K400 J013 T170 1934—(CH₂)₂— —NH—C(═O)— K400 J045 T170 1935 —(CH₂)₂— —NH—C(═O)— K400 J151T148 1936 —(CH₂)₂— —NH—C(═O)— K400 J151 T170 1937 —(CH₂)₂— —NH—C(═O)—K401 J012 T148 1938 —(CH₂)₂— —NH—C(═O)— K401 J045 T170 1939 —(CH₂)₂——NH—C(═O)— K402 J012 T148 1940 —(CH₂)₂— —NH—C(═O)— K402 J045 T170 1941—(CH₂)₂— —NH—C(═O)— K402 J151 T170 1942 —(CH₂)₂— —NH—C(═O)— K402 J159T148 1943 —(CH₂)₂— —NH—C(═O)— K402 J159 T170 1944 —(CH₂)₂— —NH—C(═O)—K403 J012 T148 1945 —(CH₂)₂— —NH—C(═O)— K403 J013 T148 1946 —(CH₂)₂——NH—C(═O)— K403 J013 T170 1947 —(CH₂)₂— —NH—C(═O)— K403 J044 T170 1948—(CH₂)₂— —NH—C(═O)— K403 J045 T170 1949 —(CH₂)₂— —NH—C(═O)— K403 J151T148 1950 —(CH₂)₂— —NH—C(═O)— K403 J151 T170 1951 —(CH₂)₂— —NH—C(═O)—K403 J158 T170 1952 —(CH₂)₂— —NH—C(═O)— K404 J012 T148 1953 —(CH₂)₂——NH—C(═O)— K405 J012 T148 1954 —(CH₂)₂— —NH—C(═O)— K406 J012 T148 1955—(CH₂)₂— —NH—C(═O)— K406 J045 T170 1956 —(CH₂)₂— —NH—C(═O)— K407 J012T148 1957 —(CH₂)₂— —NH—C(═O)— K407 J013 T148 1958 —(CH₂)₂— —NH—C(═O)—K407 J013 T170 1959 —(CH₂)₂— —NH—C(═O)— K407 J044 T170 1960 —(CH₂)₂——NH—C(═O)— K407 J045 T170 1961 —(CH₂)₂— —NH—C(═O)— K408 J012 T148 1962—(CH₂)₂— —NH—C(═O)— K409 J012 T148 1963 —(CH₂)₂— —NH—C(═O)— K409 J045T170 1964 —(CH₂)₂— —NH—C(═O)— K410 J012 T148 1965 —(CH₂)₂— —NH—C(═O)—K411 J012 T148 1966 —(CH₂)₂— —NH—C(═O)— K411 J045 T170 1967 —(CH₂)₂——NH—C(═O)— K412 J012 T148 1968 —(CH₂)₂— —NH—C(═O)— K413 J012 T148 1969—(CH₂)₂— —NH—C(═O)— K414 J012 T148 1970 —(CH₂)₂— —NH—C(═O)— K414 J044T170 1971 —(CH₂)₂— —NH—C(═O)— K414 J045 T170 1972 —(CH₂)₂— —NH—C(═O)—K415 J012 T148 1973 —(CH₂)₂— —NH—C(═O)— K415 J013 T148 1974 —(CH₂)₂——NH—C(═O)— K415 J013 T170 1975 —(CH₂)₂— —NH—C(═O)— K415 J044 T170 1976—(CH₂)₂— —NH—C(═O)— K415 J045 T170 1977 —(CH₂)₂— —NH—C(═O)— K415 J151T148 1978 —(CH₂)₂— —NH—C(═O)— K415 J151 T170 1979 —(CH₂)₂— —NH—C(═O)—K415 J158 T170 1980 —(CH₂)₂— —NH—C(═O)— K416 J012 T148 1981 —(CH₂)₂——NH—C(═O)— K417 J012 T148 1982 —(CH₂)₂— —NH—C(═O)— K418 J012 T148 1983—(CH₂)₂— —NH—C(═O)— K419 J012 T148 1984 —(CH₂)₂— —NH—C(═O)— K419 J045T170 1985 —(CH₂)₂— —NH—C(═O)— K420 J012 T148 1986 —(CH₂)₂— —NH—C(═O)—K420 J013 T148 1987 —(CH₂)₂— —NH—C(═O)— K420 J013 T170 1988 —(CH₂)₂——NH—C(═O)— K420 J044 T170 1989 —(CH₂)₂— —NH—C(═O)— K420 J045 T148 1990—(CH₂)₂— —NH—C(═O)— K420 J045 T170 1991 —(CH₂)₂— —NH—C(═O)— K420 J149T148 1992 —(CH₂)₂— —NH—C(═O)— K420 J150 T148 1993 —(CH₂)₂— —NH—C(═O)—K420 J150 T170 1994 —(CH₂)₂— —NH—C(═O)— K420 J151 T148 1995 —(CH₂)₂——NH—C(═O)— K420 J151 T170 1996 —(CH₂)₂— —NH—C(═O)— K420 J158 T170 1997—(CH₂)₂— —NH—C(═O)— K421 J012 T148 1998 —(CH₂)₂— —NH—C(═O)— K422 J012T148 1999 —(CH₂)₂— —NH—C(═O)— K423 J012 T148 2000 —(CH₂)₂— —NH—C(═O)—K424 J012 T148 2001 —(CH₂)₂— —NH—C(═O)— K425 J012 T148 2002 —(CH₂)₂——NH—C(═O)— K426 J012 T148 2003 —(CH₂)₂— —NH—C(═O)— K200 J022 T170 2004—(CH₂)₂— —NH—C(═O)— K357 J012 T148 2005 —(CH₂)₂— —NH—C(═O)—NH— K005 J045T148 2006 —(CH₂)₂— —NH—C(═O)—NH— K008 J045 T148 2007 —(CH₂)₂——NH—C(═O)—NH— K023 J012 T148 2008 —(CH₂)₂— —NH—C(═O)—NH— K033 J012 T1482009 —(CH₂)₂— —NH—C(═O)—NH— K077 J045 T148 2010 —(CH₂)₂— —NH—C(═O)—NH—K102 J045 T148 2011 —(CH₂)₂— —NH—C(═O)—NH— K102 J045 T170 2012 —(CH₂)₂——NH—C(═O)—NH— K106 J045 T148 2013 —(CH₂)₂— —NH—C(═O)—NH— K336 J012 T1482014 —(CH₂)₂— —NH—C(═O)—NH— K204 J045 T148 2015 —(CH₂)₂— —NH—C(═O)—NH—K204 J045 T170 2016 —(CH₂)₂— —NH—C(═O)—NH— K223 J045 T148 2017 —(CH₂)₂——NH—C(═O)—NH— K230 J012 T148 2018 —(CH₂)₂— —NH—C(═O)—NH— K231 J012 T1482019 —(CH₂)₂— —NH—C(═O)—NH— K248 J045 T148 2020 —(CH₂)₂— —NH—C(═O)—NH—K249 J045 T148 2021 —(CH₂)₂— —NH—C(═O)—NH— K250 J045 T148 2022 —(CH₂)₂——NH—C(═O)—NH— K278 J012 T148 2023 —(CH₂)₂— —NH—C(═O)—NH— K277 J045 T1482024 —(CH₂)₂— —NH—C(═O)—NH— K277 J045 T170 2025 —(CH₂)₂— —NH—C(═O)—NH—K278 J045 T148 2026 —(CH₂)₂— —NH—C(═O)—NH— K278 J045 T170 2027 —(CH₂)₂——NH—C(═O)—NH— K279 J045 T148 2028 —(CH₂)₂— —NH—C(═O)—NH— K286 J045 T1482029 —(CH₂)₂— —NH—C(═O)—NH— K324 J045 T148 2030 —(CH₂)₂— —NH—C(═O)—NH—K324 J045 T170 2031 —(CH₂)₂— —NH—C(═O)—NH— K325 J012 T148 2032 —(CH₂)₂——NH—C(═O)—NH— K325 J045 T148 2033 —(CH₂)₂— —NH—C(═O)—NH— K325 J045 T1702034 —(CH₂)₂— —NH—C(═O)—NH— K326 J045 T148 2035 —(CH₂)₂— —NH—C(═O)—NH—K326 J045 T169 2036 —(CH₂)₂— —NH—C(═O)—NH— K326 J045 T170 2037 —(CH₂)₂——NH—C(═O)—NH— K327 J045 T170 2038 —(CH₂)₂— —NH—C(═O)—NH— K328 J045 T1702039 —(CH₂)₂— —NH—C(═O)—NH— K329 J045 T170 2040 —(CH₂)₂— —NH—C(═O)—NH—K330 J012 T148 2041 —(CH₂)₂— —NH—C(═O)—NH— K330 J045 T170 2042 —(CH₂)₂——NH—C(═O)—NH— K331 J012 T148 2043 —(CH₂)₂— —NH—C(═O)—NH— K331 J045 T1702044 —(CH₂)₂— —NH—C(═O)—NH— K332 J045 T169 2045 —(CH₂)₂— —NH—C(═O)—NH—K332 J045 T170 2046 —(CH₂)₂— —NH—C(═O)—NH— K333 J012 T148 2047 —(CH₂)₂——NH—C(═O)—NH— K333 J044 T170 2048 —(CH₂)₂— —NH—C(═O)—NH— K333 J045 T1692049 —(CH₂)₂— —NH—C(═O)—NH— K333 J045 T170 2050 —(CH₂)₂— —NH—C(═O)—NH—K334 J045 T170 2051 —(CH₂)₂— —NH—C(═O)—NH— K335 J044 T170 2052 —(CH₂)₂——NH—C(═O)—NH— K335 J045 T148 2053 —(CH₂)₂— —NH—C(═O)—NH— K335 J045 T1702054 —(CH₂)₂— —NH—C(═O)—NH— K336 J012 T170 2055 —(CH₂)₂— —NH—C(═O)—NH—K336 J044 T170 2056 —(CH₂)₂— —NH—C(═O)—NH— K336 J045 T148 2057 —(CH₂)₂——NH—C(═O)—NH— K336 J045 T169 2058 —(CH₂)₂— —NH—C(═O)—NH— K336 J045 T1702059 —(CH₂)₂— —NH—C(═O)—NH— K337 J045 T170 2060 —(CH₂)₂— —NH—C(═O)—NH—K338 J045 T148 2061 —(CH₂)₂— —NH—C(═O)—NH— K338 J045 T170 2062 —(CH₂)₂——NH—C(═O)—NH— K339 J045 T148 2063 —(CH₂)₂— —NH—C(═O)—NH— K339 J045 T1702064 —(CH₂)₂— —NH—C(═O)—NH— K340 J012 T148 2065 —(CH₂)₂— —NH—C(═O)—NH—K340 J045 T148 2066 —(CH₂)₂— —NH—C(═O)—NH— K340 J045 T169 2067 —(CH₂)₂——NH—C(═O)—NH— K340 J045 T170 2068 —(CH₂)₂— —NH—C(═O)—NH— K341 J045 T1482069 —(CH₂)₂— —NH—C(═O)—NH— K341 J045 T170 2070 —(CH₂)₂— —NH—C(═O)—NH—K342 J045 T148 2071 —(CH₂)₂— —NH—C(═O)—NH— K342 J045 T170 2072 —(CH₂)₂——NH—C(═O)—NH— K343 J045 T148 2073 —(CH₂)₂— —NH—C(═O)—NH— K343 J045 T1702074 —(CH₂)₂— —NH—C(═O)—NH— K344 J045 T170 2075 —(CH₂)₂— —NH—C(═O)—NH—K345 J045 T170 2076 —(CH₂)₂— —NH—C(═O)—NH— K346 J045 T170 2077 —(CH₂)₂——NH—C(═O)—NH— K347 J045 T170 2078 —(CH₂)₂— —NH—C(═O)—NH— K348 J045 T1482079 —(CH₂)₂— —NH—C(═O)—NH— K348 J045 T170 2080 —(CH₂)₂— —NH—C(═O)—NH—K349 J045 T170 2081 —(CH₂)₂— —NH—C(═O)—NH— K350 J045 T148 2082 —(CH₂)₂——NH—C(═O)—NH— K350 J045 T170 2083 —(CH₂)₂— —NH—C(═O)—NH— K351 J045 T1482084 —(CH₂)₂— —NH—C(═O)—NH— K351 J045 T170 2085 —(CH₂)₂— —NH—C(═O)—NH—K352 J045 T148 2086 —(CH₂)₂— —NH—C(═O)—NH— K352 J045 T170 2087 —(CH₂)₂——NH—C(═O)—NH— K353 J045 T148 2088 —(CH₂)₂— —NH—C(═O)—NH— K353 J045 T1702089 —(CH₂)₂— —NH—C(═O)—NH— K354 J045 T148 2090 —(CH₂)₂— —NH—C(═O)—NH—K354 J045 T170 2091 —(CH₂)₂— —NH—C(═O)—NH— K355 J045 T170 2092 —(CH₂)₂——NH—C(═O)—NH— K356 J045 T170 2093 —(CH₂)₂— —NH—C(═O)—NH— K359 J045 T1482094 —(CH₂)₂— —NH—C(═O)—NH— K360 J045 T148 2095 —(CH₂)₂— —NH—C(═O)—NH—K362 J045 T148 2096 —(CH₂)₂— —NH—C(═O)—NH— K361 J045 T148 2097 —(CH₂)₂——NH—C(═O)—NH— K362 J045 T170 2098 —(CH₂)₂— —NH—C(═O)—NH— K364 J045 T1702099 —(CH₂)₂— —NH—C(═O)—NH— K370 J045 T148 2100 —(CH₂)₂— —NH—C(═O)—NH—K371 J045 T148 2101 —(CH₂)₂— —NH—C(═O)—NH— K373 J045 T148 2102 —(CH₂)₂——NH—C(═O)—NH— K431 J045 T170 2103 —(CH₂)₂— —NH—C(═O)—NH— K395 J012 T1482104 —(CH₂)₂— —NH—C(═O)—NH— K395 J045 T170 2105 —(CH₂)₂— —NH—C(═O)—NH—K396 J012 T148 2106 —(CH₂)₂— —NH—C(═O)—NH— K396 J045 T170 2107 —(CH₂)₂——NH—C(═O)—NH— K397 J012 T148 2108 —(CH₂)₂— —NH—C(═O)—NH— K397 J045 T1702109 —(CH₂)₂— —NH—C(═O)— K241 J045 T148 2110 —(CH₂)₂— —NH—C(═O)—O— K005J001 T148 2111 —(CH₂)₂— —NH—C(═O)—O— K005 J007 T148 2112 —(CH₂)₂——NH—C(═O)—O— K005 J008 T148 2113 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T1702114 —(CH₂)₂— —NH—C(═O)—O— K005 J010 T148 2115 —(CH₂)₂— —NH—C(═O)—O—K005 J011 T170 2116 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T170 2117 —(CH₂)₂——NH—C(═O)—O— K005 J013 T148 2118 —(CH₂)₂— —NH—C(═O)—O— K005 J014 T1482119 —(CH₂)₂— —NH—C(═O)—O— K005 J015 T170 2120 —(CH₂)₂— —NH—C(═O)—O—K005 J026 T001 2121 —(CH₂)₂— —NH—C(═O)—O— K005 J026 T148 2122 —(CH₂)₂——NH—C(═O)—O— K005 J026 T170 2123 —(CH₂)₂— —NH—C(═O)—O— K005 J037 T1702124 —(CH₂)₂— —NH—C(═O)—O— K005 J039 T170 2125 —(CH₂)₂— —NH—C(═O)—O—K005 J043 T170 2126 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T072 2127 —(CH₂)₂——NH—C(═O)—O— K005 J045 T074 2128 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T1802129 —(CH₂)₂— —NH—C(═O)—O— K005 J047 T170 2130 —(CH₂)₂— —NH—C(═O)—O—K005 J079 T170 2131 —(CH₂)₂— —NH—C(═O)—O— K005 J080 T148 2132 —(CH₂)₂——NH—C(═O)—O— K005 J081 T148 2133 —(CH₂)₂— —NH—C(═O)—O— K005 J082 T1482134 —(CH₂)₂— —NH—C(═O)—O— K005 J090 T148 2135 —(CH₂)₂— —NH—C(═O)—O—K005 J092 T148 2136 —(CH₂)₂— —NH—C(═O)—O— K005 J103 T170 2137 —(CH₂)₂——NH—C(═O)—O— K005 J104 T170 2138 —(CH₂)₂— —NH—C(═O)—O— K005 J105 T1702139 —(CH₂)₂— —NH—C(═O)—O— K005 J106 T170 2140 —(CH₂)₂— —NH—C(═O)—O—K005 J107 T170 2141 —(CH₂)₂— —NH—C(═O)—O— K005 J140 T001 2142 —(CH₂)₂——NH—C(═O)—O— K005 J140 T148 2143 —(CH₂)₂— —NH—C(═O)—O— K005 J140 T1702144 —(CH₂)₂— —NH—C(═O)—O— K005 J144 T148 2145 —(CH₂)₂— —NH—C(═O)—O—K005 J146 T148 2146 —(CH₂)₂— —NH—C(═O)—O— K199 J045 T148 2147 —(CH₂)₂——NH—C(═O)—O— K223 J045 T148 2148 —(CH₂)₂— —NH—C(═O)—O— K198 J045 T1482149 —(CH₂)₂— —NH—S(═O)₂— K200 J012 T148 2150 —(CH₂)₂— —NH—S(═O)₂— K200J044 T170 2151 —(CH₂)₂— —NH—S(═O)₂— K200 J045 T170 2152 —(CH₂)₂——NH—S(═O)₂— K223 J012 T148 2153 —(CH₂)₂— —NH—S(═O)₂— K223 J044 T170 2154—(CH₂)₂— —NH—S(═O)₂— K230 J044 T170 2155 —(CH₂)₂— —NH—S(═O)₂— K230 J045T170 2156 —(CH₂)₂— —NH—S(═O)₂— K231 J044 T170 2157 —(CH₂)₂— —NH—S(═O)₂—K231 J045 T170 2158 —(CH₂)₃— —C(═O)— K108 J001 T148 2159 —(CH₂)₃——C(═O)— K108 J022 T170 2160 —(CH₂)₃— —C(═O)— K109 J029 T170 2161—(CH₂)₃— —C(═O)— K112 J012 T148 2162 —(CH₂)₃— —C(═O)— K112 J012 T1702163 —(CH₂)₃— —C(═O)— K112 J037 T170 2164 —(CH₂)₃— —C(═O)— K112 J043T170 2165 —(CH₂)₃— —C(═O)— K112 J138 T148 2166 —(CH₂)₃— —C(═O)— K112J138 T170 2167 —(CH₂)₃— —C(═O)— K112 J144 T148 2168 —(CH₂)₃— —C(═O)—K112 J144 T164 2169 —(CH₂)₃— —C(═O)— K112 J144 T169 2170 —(CH₂)₃——C(═O)— K112 J144 T170 2171 —(CH₂)₃— —C(═O)— K116 J012 T148 2172—(CH₂)₃— —C(═O)— K121 J043 T170 2173 —(CH₂)₃— —C(═O)— K129 J012 T1482174 —(CH₂)₃— —C(═O)— K136 J044 T170 2175 —(CH₂)₃— —C(═O)— K137 J012T148 2176 —(CH₂)₃— —C(═O)— K137 J012 T170 2177 —(CH₂)₃— —C(═O)— K137J045 T170 2178 —(CH₂)₃— —C(═O)— K138 J079 T170 2179 —(CH₂)₃— —C(═O)—K139 J012 T148 2180 —(CH₂)₃— —C(═O)— K142 J012 T148 2181 —(CH₂)₃——C(═O)— K143 J012 T148 2182 —(CH₂)₃— —C(═O)— K144 J012 T148 2183—(CH₂)₃— —C(═O)— K144 J043 T148 2184 —(CH₂)₃— —C(═O)— K144 J043 T1702185 —(CH₂)₃— —C(═O)— K144 J138 T148 2186 —(CH₂)₃— —C(═O)— K144 J138T170 2187 —(CH₂)₃— —C(═O)— K144 J144 T148 2188 —(CH₂)₃— —C(═O)— K144J144 T170 2189 —(CH₂)₃— —C(═O)— K147 J012 T148 2190 —(CH₂)₃— —C(═O)—K147 J138 T170 2191 —(CH₂)₃— —C(═O)— K148 J012 T148 2192 —(CH₂)₃——C(═O)— K148 J139 T170 2193 —(CH₂)₃— —C(═O)— K150 J012 T148 2194—(CH₂)₃— —C(═O)— K154 J012 T148 2195 —(CH₂)₃— —C(═O)— K166 J012 T1482196 —(CH₂)₃— —C(═O)— K166 J144 T170 2197 —(CH₂)₃— —C(═O)— K170 J007T170 2198 —(CH₂)₃— —C(═O)— K172 J012 T170 2199 —(CH₂)₃— —C(═O)— K237J012 T148 2200 —(CH₂)₃— —C(═O)— K391 J144 T170 2201 —(CH₂)₃— —C(═O)—NH—K004 J012 T148 2202 —(CH₂)₃— —C(═O)—NH— K009 J001 T148 2203 —(CH₂)₃——C(═O)—NH— K009 J007 T148 2204 —(CH₂)₃— —C(═O)—NH— K009 J007 T164 2205—(CH₂)₃— —C(═O)—NH— K009 J007 T169 2206 —(CH₂)₃— —C(═O)—NH— K009 J007T170 2207 —(CH₂)₃— —C(═O)—NH— K009 J012 T148 2208 —(CH₂)₃— —C(═O)—NH—K009 J037 T170 2209 —(CH₂)₃— —C(═O)—NH— K012 J001 T148 2210 —(CH₂)₃——C(═O)—NH— K013 J012 T148 2211 —(CH₂)₃— —C(═O)—NH— K013 J012 T170 2212—(CH₂)₃— —C(═O)—NH— K023 J012 T148 2213 —(CH₂)₃— —C(═O)—NH— K023 J029T148 2214 —(CH₂)₃— —C(═O)—NH— K023 J029 T164 2215 —(CH₂)₃— —C(═O)—NH—K023 J029 T169 2216 —(CH₂)₃— —C(═O)—NH— K023 J029 T170 2217 —(CH₂)₃——C(═O)—NH— K023 J043 T170 2218 —(CH₂)₃— —C(═O)—NH— K029 J012 T148 2219—(CH₂)₃— —C(═O)—NH— K029 J044 T148 2220 —(CH₂)₃— —C(═O)—NH— K029 J044T164 2221 —(CH₂)₃— —C(═O)—NH— K029 J044 T169 2222 —(CH₂)₃— —C(═O)—NH—K029 J044 T170 2223 —(CH₂)₃— —C(═O)—NH— K029 J045 T170 2224 —(CH₂)₃——C(═O)—NH— K033 J012 T148 2225 —(CH₂)₃— —C(═O)—NH— K033 J043 T148 2226—(CH₂)₃— —C(═O)—NH— K033 J043 T164 2227 —(CH₂)₃— —C(═O)—NH— K033 J043T169 2228 —(CH₂)₃— —C(═O)—NH— K033 J043 T170 2229 —(CH₂)₃— —C(═O)—NH—K033 J044 T170 2230 —(CH₂)₃— —C(═O)—NH— K034 J012 T148 2231 —(CH₂)₃——C(═O)—NH— K034 J045 T148 2232 —(CH₂)₃— —C(═O)—NH— K034 J045 T164 2233—(CH₂)₃— —C(═O)—NH— K034 J045 T169 2234 —(CH₂)₃— —C(═O)—NH— K034 J045T170 2235 —(CH₂)₃— —C(═O)—NH— K034 J079 T170 2236 —(CH₂)₃— —C(═O)—NH—K077 J138 T170 2237 —(CH₂)₃— —C(═O)—NH— K078 J139 T170 2238 —(CH₂)₃——C(═O)—NH— K101 J144 T170 2239 —(CH₂)₃— —C(═O)—NH— K102 J007 T170 2240—(CH₂)₃— —C(═O)—NH— K102 J012 T148 2241 —(CH₂)₃— —C(═O)—NH— K102 J012T170 2242 —(CH₂)₃— —C(═O)—NH— K102 J079 T148 2243 —(CH₂)₃— —C(═O)—NH—K102 J079 T164 2244 —(CH₂)₃— —C(═O)—NH— K102 J079 T169 2245 —(CH₂)₃——C(═O)—NH— K102 J079 T170 2246 —(CH₂)₃— —C(═O)—NH— K103 J012 T148 2247—(CH₂)₃— —C(═O)—NH— K103 J138 T148 2248 —(CH₂)₃— —C(═O)—NH— K103 J138T164 2249 —(CH₂)₃— —C(═O)—NH— K103 J138 T169 2250 —(CH₂)₃— —C(═O)—NH—K103 J138 T170 2251 —(CH₂)₃— —C(═O)—NH— K104 J012 T148 2252 —(CH₂)₃——C(═O)—NH— K104 J012 T170 2253 —(CH₂)₃— —C(═O)—NH— K104 J139 T148 2254—(CH₂)₃— —C(═O)—NH— K104 J139 T164 2255 —(CH₂)₃— —C(═O)—NH— K104 J139T169 2256 —(CH₂)₃— —C(═O)—NH— K104 J139 T170 2257 —(CH₂)₃— —C(═O)—NH—K108 J012 T148 2258 —(CH₂)₃— —C(═O)—NH— K198 J012 T148 2259 —(CH₂)₃——C(═O)—NH— K198 J022 T170 2260 —(CH₂)₃— —C(═O)—NH— K200 J012 T148 2261—(CH₂)₃— —C(═O)—NH— K200 J029 T170 2262 —(CH₂)₃— —C(═O)—NH— K201 J012T148 2263 —(CH₂)₃— —C(═O)—NH— K201 J037 T170 2264 —(CH₂)₃— —C(═O)—NH—K204 J002 T148 2265 —(CH₂)₃— —C(═O)—NH— K204 J012 T148 2266 —(CH₂)₃——C(═O)—NH— K204 J012 T170 2267 —(CH₂)₃— —C(═O)—NH— K204 J043 T148 2268—(CH₂)₃— —C(═O)—NH— K204 J043 T170 2269 —(CH₂)₃— —C(═O)—NH— K204 J138T170 2270 —(CH₂)₃— —C(═O)—NH— K204 J139 T148 2271 —(CH₂)₃— —C(═O)—NH—K204 J144 T148 2272 —(CH₂)₃— —C(═O)—NH— K204 J144 T170 2273 —(CH₂)₃——C(═O)—NH— K215 J012 T148 2274 —(CH₂)₃— —C(═O)—NH— K216 J007 T170 2275—(CH₂)₃— —C(═O)—NH— K216 J012 T148 2276 —(CH₂)₃— —C(═O)—NH— K216 J012T164 2277 —(CH₂)₃— —C(═O)—NH— K216 J012 T170 2278 —(CH₂)₃— —C(═O)—NH—K216 J022 T170 2279 —(CH₂)₃— —C(═O)—NH— K216 J029 T170 2280 —(CH₂)₃——C(═O)—NH— K216 J037 T170 2281 —(CH₂)₃— —C(═O)—NH— K216 J043 T148 2282—(CH₂)₃— —C(═O)—NH— K216 J043 T170 2283 —(CH₂)₃— —C(═O)—NH— K216 J044T169 2284 —(CH₂)₃— —C(═O)—NH— K216 J044 T170 2285 —(CH₂)₃— —C(═O)—NH—K216 J045 T170 2286 —(CH₂)₃— —C(═O)—NH— K216 J079 T170 2287 —(CH₂)₃——C(═O)—NH— K216 J138 T148 2288 —(CH₂)₃— —C(═O)—NH— K216 J138 T170 2289—(CH₂)₃— —C(═O)—NH— K216 J139 T170 2290 —(CH₂)₃— —C(═O)—NH— K216 J144T148 2291 —(CH₂)₃— —C(═O)—NH— K216 J144 T170 2292 —(CH₂)₃— —C(═O)—NH—K223 J001 T148 2293 —(CH₂)₃— —C(═O)—NH— K223 J045 T170 2294 —(CH₂)₃——C(═O)—NH— K224 J079 T170 2295 —(CH₂)₃— —C(═O)—NH— K225 J138 T170 2296—(CH₂)₃— —C(═O)—NH— K229 J012 T148 2297 —(CH₂)₃— —C(═O)—NH— K229 J139T170 2298 —(CH₂)₃— —C(═O)—NH— K234 J012 T148 2299 —(CH₂)₃— —C(═O)—NH—K198 J001 T148 2300 —(CH₂)₃— —C(═O)—NH— K244 J001 T148 2301 —(CH₂)₃——C(═O)—NH— K246 J001 T148 2302 —(CH₂)₃— —C(═O)—NH— K280 J012 T148 2303—(CH₂)₃— —C(═O)—NH— K293 J144 T170 2304 —(CH₂)₃— —C(═O)—NH— K323 J007T170 2305 —(CH₂)₃— —C(═O)—NH— K324 J012 T148 2306 —(CH₂)₃— —C(═O)—NH—K324 J012 T170 2307 —(CH₂)₃— —C(═O)—NH— K325 J022 T170 2308 —(CH₂)₃——C(═O)—NH— K326 J029 T170 2309 —(CH₂)₃— —C(═O)—NH— K327 J037 T170 2310—(CH₂)₃— —C(═O)—NH— K333 J007 T170 2311 —(CH₂)₃— —C(═O)—NH— K333 J012T148 2312 —(CH₂)₃— —C(═O)—NH— K333 J012 T170 2313 —(CH₂)₃— —C(═O)—NH—K333 J022 T170 2314 —(CH₂)₃— —C(═O)—NH— K333 J029 T170 2315 —(CH₂)₃——C(═O)—NH— K333 J037 T170 2316 —(CH₂)₃— —C(═O)—NH— K333 J043 T170 2317—(CH₂)₃— —C(═O)—NH— K333 J044 T170 2318 —(CH₂)₃— —C(═O)—NH— K333 J045T170 2319 —(CH₂)₃— —C(═O)—NH— K333 J079 T170 2320 —(CH₂)₃— —C(═O)—NH—K333 J138 T170 2321 —(CH₂)₃— —C(═O)—NH— K333 J139 T170 2322 —(CH₂)₃——C(═O)—NH— K333 J144 T170 2323 —(CH₂)₃— —C(═O)—NH— K334 J043 T170 2324—(CH₂)₃— —C(═O)—NH— K335 J044 T170 2325 —(CH₂)₃— —C(═O)—NH— K336 J012T148 2326 —(CH₂)₃— —C(═O)—NH— K340 J045 T170 2327 —(CH₂)₃— —C(═O)—NH—K343 J012 T148 2328 —(CH₂)₃— —C(═O)—NH— K343 J079 T170 2329 —(CH₂)₃——C(═O)—NH— K344 J012 T148 2330 —(CH₂)₃— —C(═O)—NH— K346 J007 T170 2331—(CH₂)₃— —C(═O)—NH— K346 J012 T148 2332 —(CH₂)₃— —C(═O)—NH— K346 J012T170 2333 —(CH₂)₃— —C(═O)—NH— K346 J022 T170 2334 —(CH₂)₃— —C(═O)—NH—K346 J029 T170 2335 —(CH₂)₃— —C(═O)—NH— K346 J037 T170 2336 —(CH₂)₃——C(═O)—NH— K346 J043 T148 2337 —(CH₂)₃— —C(═O)—NH— K346 J043 T170 2338—(CH₂)₃— —C(═O)—NH— K346 J044 T170 2339 —(CH₂)₃— —C(═O)—NH— K346 J045T170 2340 —(CH₂)₃— —C(═O)—NH— K346 J079 T170 2341 —(CH₂)₃— —C(═O)—NH—K346 J080/J081 T148 2342 —(CH₂)₃— —C(═O)—NH— K346 J090 T148 2343—(CH₂)₃— —C(═O)—NH— K346 J100 T148 2344 —(CH₂)₃— —C(═O)—NH— K346 J138T148 2345 —(CH₂)₃— —C(═O)—NH— K346 J138 T170 2346 —(CH₂)₃— —C(═O)—NH—K346 J139 T170 2347 —(CH₂)₃— —C(═O)—NH— K346 J144 T148 2348 —(CH₂)₃——C(═O)—NH— K346 J144 T170 2349 —(CH₂)₃— —C(═O)—NH— K347 J138 T170 2350—(CH₂)₃— —C(═O)—NH— K353 J012 T148 2351 —(CH₂)₃— —C(═O)—NH— K370 J139T170 2352 —(CH₂)₃— —C(═O)—NH— K427 J012 T148 2353 —(CH₂)₃— —C(═O)—NH—K428 J045 T170 2354 —(CH₂)₃— —C(═O)—NH— K429 J012 T148 2355 —(CH₂)₃——C(═O)—NH— K430 J045 T170 2356 —(CH₂)₃— —C(═O)— K240 J012 T148 2357—(CH₂)₃— —C(═O)— K240 J012 T170 2358 —(CH₂)₃— —C(═O)—O— K001 J002 T1482359 —(CH₂)₃— —C(═O)—O— K001 J007 T170 2360 —(CH₂)₃— —C(═O)—O— K001 J012T148 2361 —(CH₂)₃— —C(═O)—O— K002 J044 T170 2362 —(CH₂)₃— —C(═O)—O— K197J002 T148 2363 —(CH₂)₃— —C(═O)—O— K197 J012 T148 2364 —(CH₂)₃— —C(═O)—O—K197 J012 T170 2365 —(CH₂)₃— —C(═O)—O— K197 J045 T170 2366 —(CH₂)₃— —NH—K185 J007 T148 2367 —(CH₂)₃— —NH— K185 J044 T170 2368 —(CH₂)₃——NH—C(═O)— K005 J007 T148 2369 —(CH₂)₃— —NH—C(═O)— K005 J044 T170 2370—(CH₂)₃— —NH—C(═O)— K007 J012 T148 2371 —(CH₂)₃— —NH—C(═O)— K007 J045T170 2372 —(CH₂)₃— —NH—C(═O)— K008 J012 T148 2373 —(CH₂)₃— —NH—C(═O)—K008 J045 T170 2374 —(CH₂)₃— —NH—C(═O)— K009 J007 T148 2375 —(CH₂)₃——NH—C(═O)— K009 J044 T170 2376 —(CH₂)₃— —NH—C(═O)— K011 J007 T148 2377—(CH₂)₃— —NH—C(═O)— K011 J044 T170 2378 —(CH₂)₃— —NH—C(═O)— K013 J007T148 2379 —(CH₂)₃— —NH—C(═O)— K013 J044 T170 2380 —(CH₂)₃— —NH—C(═O)—K051 J012 T148 2381 —(CH₂)₃— —NH—C(═O)— K051 J045 T170 2382 —(CH₂)₃——NH—C(═O)— K200 J012 T148 2383 —(CH₂)₃— —NH—C(═O)— K200 J045 T170 2384—(CH₂)₃— —NH—C(═O)— K204 J007 T148 2385 —(CH₂)₃— —NH—C(═O)— K204 J044T170 2386 —(CH₂)₃— —NH—C(═O)— K208 J012 T148 2387 —(CH₂)₃— —NH—C(═O)—K208 J045 T170 2388 —(CH₂)₃— —NH—C(═O)— K212 J012 T148 2389 —(CH₂)₃——NH—C(═O)— K212 J045 T170 2390 —(CH₂)₃— —NH—C(═O)— K262 J012 T148 2391—(CH₂)₃— —NH—C(═O)— K262 J045 T170 2392 —(CH₂)₃— —NH—C(═O)— K263 J007T148 2393 —(CH₂)₃— —NH—C(═O)— K263 J044 T170 2394 —(CH₂)₃— —NH—C(═O)—K266 J007 T148 2395 —(CH₂)₃— —NH—C(═O)— K266 J044 T170 2396 —(CH₂)₃——NH—C(═O)— K272 J012 T148 2397 —(CH₂)₃— —NH—C(═O)— K272 J045 T170 2398—(CH₂)₃— —NH—C(═O)— K293 J007 T148 2399 —(CH₂)₃— —NH—C(═O)— K293 J044T170 2400 —(CH₂)₃— —NH—C(═O)—NH— K033 J012 T148 2401 —(CH₂)₃——NH—C(═O)—NH— K033 J045 T170 2402 —(CH₂)₃— —NH—C(═O)—NH— K333 J007 T1482403 —(CH₂)₃— —NH—C(═O)—NH— K333 J044 T170 2404 —(CH₂)₃— —NH—C(═O)—NH—K336 J012 T148 2405 —(CH₂)₃— —NH—C(═O)—NH— K336 J045 T170 2406 Singlebond Single bond K001 J002 T170 2407 Single bond Single bond K001 J007T148 2408 Single bond Single bond K001 J007 T170 2409 Single bond Singlebond K001 J012 T148 2410 Single bond Single bond K001 J012 T170 2411Single bond Single bond K001 J029 T148 2412 Single bond Single bond K001J029 T170 2413 Single bond Single bond K001 J037 T148 2414 Single bondSingle bond K001 J037 T170 2415 Single bond Single bond K001 J043 T1482416 Single bond Single bond K001 J043 T170 2417 Single bond Single bondK001 J044 T148 2418 Single bond Single bond K001 J044 T170 2419 Singlebond Single bond K001 J045 T148 2420 Single bond Single bond K001 J045T170 2421 Single bond Single bond K001 J138 T148 2422 Single bond Singlebond K001 J138 T170 2423 Single bond Single bond K001 J144 T148 2424Single bond Single bond K001 J144 T170 2425 Single bond Single bond K002J012 T148 2426 Single bond Single bond K002 J012 T170 2427 Single bondSingle bond K002 J044 T148 2428 Single bond Single bond K002 J044 T1702429 Single bond Single bond K002 J045 T170 2430 Single bond Single bondK002 J139 T148 2431 Single bond Single bond K002 J139 T170 2432 Singlebond Single bond K197 J002 T148 2433 Single bond Single bond K197 J002T170 2434 Single bond Single bond K197 J007 T148 2435 Single bond Singlebond K197 J007 T170 2436 Single bond Single bond K197 J008 T148 2437Single bond Single bond K197 J008 T170 2438 Single bond Single bond K197J010 T148 2439 Single bond Single bond K197 J010 T170 2440 Single bondSingle bond K197 J012 T170 2441 Single bond Single bond K197 J013 T1482442 Single bond Single bond K197 J013 T170 2443 Single bond Single bondK197 J014 T148 2444 Single bond Single bond K197 J014 T170 2445 Singlebond Single bond K197 J018 T148 2446 Single bond Single bond K197 J022T148 2447 Single bond Single bond K197 J022 T170 2448 Single bond Singlebond K197 J026 T148 2449 Single bond Single bond K197 J026 T170 2450Single bond Single bond K197 J027 T148 2451 Single bond Single bond K197J027 T170 2452 Single bond Single bond K197 J028 T148 2453 Single bondSingle bond K197 J028 T170 2454 Single bond Single bond K197 J029 T1482455 Single bond Single bond K197 J029 T169 2456 Single bond Single bondK197 J029 T170 2457 Single bond Single bond K197 J030 T148 2458 Singlebond Single bond K197 J030 T170 2459 Single bond Single bond K197 J031T148 2460 Single bond Single bond K197 J031 T170 2461 Single bond Singlebond K197 J032 T148 2462 Single bond Single bond K197 J032 T170 2463Single bond Single bond K197 J034 T148 2464 Single bond Single bond K197J034 T170 2465 Single bond Single bond K197 J036 T148 2466 Single bondSingle bond K197 J036 T170 2467 Single bond Single bond K197 J037 T1482468 Single bond Single bond K197 J037 T170 2469 Single bond Single bondK197 J039 T148 2470 Single bond Single bond K197 J039 T170 2471 Singlebond Single bond K197 J043 T148 2472 Single bond Single bond K197 J043T170 2473 Single bond Single bond K197 J044 T148 2474 Single bond Singlebond K197 J044 T170 2475 Single bond Single bond K197 J045 T148 2476Single bond Single bond K197 J045 T170 2477 Single bond Single bond K197J090 T148 2478 Single bond Single bond K197 J090 T170 2479 Single bondSingle bond K197 J092 T148 2480 Single bond Single bond K197 J092 T1702481 Single bond Single bond K197 J144 T148 2482 Single bond Single bondK197 J121 T148 2483 Single bond Single bond K197 J121 T170 2484 Singlebond Single bond K197 J137 T148 2485 Single bond Single bond K197 J137T170 2486 Single bond Single bond K197 J138 T148 2487 Single bond Singlebond K197 J138 T170 2488 Single bond Single bond K197 J139 T148 2489Single bond Single bond K197 J139 T170 2490 Single bond Single bond K197J141 T148 2491 Single bond Single bond K197 J141 T170 2492 Single bondSingle bond K197 J142 T148 2493 Single bond Single bond K197 J142 T1692494 Single bond Single bond K197 J142 T170 2495 Single bond Single bondK197 J143 T148 2496 Single bond Single bond K197 J143 T170 2497 Singlebond Single bond K197 J107 T148 2498 Single bond Single bond K197 J144T170 2499 Single bond Single bond K223 J001 T164 2500 Single bond Singlebond K223 J138 T148 2501 —(CH₂)₃— —C(═O)—O— K002 J001 T001 2502 —(CH₂)₃——C(═O)—O— K002 J001 T005 2503 —(CH₂)₃— —C(═O)—O— K197 J001 T148 2504—(CH₂)₃— —C(═O)—O— K002 J002 T148 2505 —(CH₂)₃— —C(═O)—O— K197 J002 T1702506 —(CH₂)₃— —C(═O)—NH— K346 J002 T170 2507 —(CH₂)₃— —C(═O)—O— K002J012 T001 2508 —(CH₂)₃— —C(═O)—O— K002 J012 T005 2509 —(CH₂)₃— —C(═O)—O—K002 J012 T148 2510 —(CH₂)₃— —C(═O)—O— K002 J012 T170 2511 —(CH₂)₂——NH—C(═O)— K005 J012 T004 2512 —(CH₂)₃— —C(═O)—O— K002 J001 T148 2513—(CH₂)₂— —NH—C(═O)—O— K005 J045 T181 2514 —(CH₂)₂— —NH—C(═O)— K338 J012T148

Also, among compounds described in Table 1, compounds of the followingnumbers are more preferred.

Compound numbers 19, 20, 22, 27, 29, 30, 34, 36, 37, 38, 39, 40, 41, 42,43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62,63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 81, 84, 85,86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 104,105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120,121, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135,136, 137, 138, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151,152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166,167, 168, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182,183, 184, 185, 186, 187, 188, 190, 191, 192, 193, 194, 195, 196, 197,198, 200, 201, 202, 203, 206, 210, 211, 213, 214, 217, 219, 221, 223,225, 226, 227, 228, 229, 230, 231, 232, 237, 240, 241, 242, 243, 244,245, 250, 253, 254, 255, 257, 258, 260, 261, 262, 263, 265, 266, 267,268, 269, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286,287, 288, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 308, 309,310, 311, 312, 313, 314, 315, 316, 317, 320, 321, 327, 328, 330, 331,332, 333, 334, 335, 340, 342, 343, 348, 349, 350, 351, 352, 353, 359,361, 362, 363, 364, 365, 366, 368, 369, 371, 373, 379, 381, 382, 383,384, 385, 386, 387, 392, 393, 395, 397, 398, 399, 400, 401, 407, 409,410, 411, 412, 413, 415, 416, 417, 418, 419, 420, 421, 422, 423, 426,427, 429, 430, 431, 432, 433, 434, 437, 438, 439, 445, 447, 448, 449,451, 453, 454, 455, 456, 457, 463, 465, 466, 467, 468, 469, 471, 472,473, 474, 475, 476, 477, 478, 479, 483, 484, 485, 486, 487, 488, 489,490, 491, 492, 493, 494, 497, 498, 499, 501, 502, 503, 504, 509, 511,512, 513, 515, 517, 518, 519, 520, 521, 527, 529, 530, 531, 532, 533,534, 535, 536, 537, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549,550, 551, 552, 555, 556, 557, 563, 565, 566, 567, 569, 571, 572, 573,574, 575, 581, 583, 584, 585, 586, 587, 589, 590, 591, 593, 594, 595,596, 597, 599, 600, 601, 602, 605, 606, 607, 608, 610, 611, 612, 613,615, 616, 617, 618, 620, 621, 623, 624, 625, 626, 627, 628, 629, 630,631, 634, 635, 638, 639, 641, 642, 643, 644, 645, 646, 647, 648, 651,652, 653, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,667, 668, 669, 670, 671, 672, 673, 675, 676, 677, 678, 679, 681, 682,683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696,697, 700, 701, 702, 704, 705, 706, 707, 709, 710, 711, 712, 713, 715,716, 717, 718, 719, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730,731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 743, 744, 745,747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760,761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 773, 776, 777,778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791,792, 793, 794, 795, 796, 801, 802, 803, 804, 805, 806, 807, 808, 809,810, 811, 812, 852, 853, 874, 892, 893, 915, 917, 918, 919, 921, 939,946, 998, 1000, 1001, 1002, 1007, 1008, 1014, 1015, 1054, 1055, 1056,1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1076, 1077, 1078,1079, 1080, 1081, 1083, 1085, 1089, 1090, 1091, 1092, 1093, 1095, 1096,1097, 1098, 1099, 1103, 1104, 1106, 1110, 1112, 1113, 1115, 1117, 1118,1120, 1121, 1127, 1129, 1130, 1131, 1132, 1134, 1137, 1140, 1143, 1146,1151, 1152, 1153, 1155, 1156, 1158, 1159, 1161, 1165, 1166, 1167, 1168,1170, 1178, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190,1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202,1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214,1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226,1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238,1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250,1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262,1263, 1264, 1265, 1266, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275,1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287,1288, 1289, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300,1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312,1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324,1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336,1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348,1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360,1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372,1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384,1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396,1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408,1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420,1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432,1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444,1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456,1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468,1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480,1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492,1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504,1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516,1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528,1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540,1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552,1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564,1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576,1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588,1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600,1601, 1602, 1603, 1604, 1605, 1606, 1607, 1608, 1609, 1610, 1611, 1612,1613, 1614, 1615, 1616, 1617, 1618, 1619, 1620, 1621, 1622, 1623, 1624,1625, 1626, 1627, 1628, 1629, 1630, 1631, 1632, 1633, 1634, 1635, 1636,1637, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1648,1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1658, 1659, 1660,1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672,1673, 1674, 1675, 1676, 1677, 1678, 1679, 1680, 1681, 1682, 1683, 1684,1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696,1697, 1698, 1700, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709,1710, 1711, 1712, 1713, 1714, 1715, 1716, 1717, 1718, 1719, 1720, 1721,1722, 1723, 1724, 1725, 1726, 1727, 1728, 1729, 1730, 1731, 1732, 1733,1734, 1735, 1736, 1737, 1738, 1739, 1740, 1741, 1742, 1743, 1744, 1745,1746, 1747, 1748, 1749, 1750, 1751, 1752, 1753, 1754, 1755, 1756, 1757,1758, 1759, 1760, 1761, 1762, 1763, 1764, 1765, 1766, 1767, 1768, 1769,1770, 1771, 1772, 1773, 1774, 1775, 1776, 1777, 1778, 1779, 1780, 1781,1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 1790, 1791, 1792, 1793,1794, 1795, 1796, 1797, 1798, 1799, 1800, 1801, 1802, 1803, 1804, 1805,1806, 1807, 1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817,1818, 1819, 1820, 1821, 1822, 1823, 1824, 1825, 1826, 1827, 1829, 1830,1831, 1832, 1833, 1834, 1835, 1836, 1837, 1838, 1839, 1840, 1841, 1842,1843, 1844, 1845, 1846, 1847, 1848, 1849, 1850, 1851, 1852, 1853, 1854,1855, 1856, 1857, 1858, 1859, 1860, 1861, 1862, 1863, 1864, 1865, 1866,1867, 1868, 1869, 1870, 1871, 1872, 1873, 1874, 1875, 1876, 1877, 1878,1879, 1880, 1881, 1882, 1883, 1884, 1885, 1886, 1887, 1888, 1889, 1890,1891, 1892, 1893, 1894, 1895, 1896, 1897, 1898, 1899, 1900, 1901, 1902,1903, 1904, 1905, 1906, 1907, 1908, 1909, 1910, 1911, 1912, 1913, 1914,1915, 1916, 1917, 1918, 1919, 1920, 1921, 1922, 1923, 1924, 1925, 1926,1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1935, 1936, 1937, 1938,1939, 1940, 1941, 1942, 1943, 1944, 1945, 1946, 1947, 1948, 1949, 1950,1951, 1952, 1953, 1954, 1955, 1956, 1957, 1958, 1959, 1960, 1961, 1962,1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 1972, 1973, 1974,1975, 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986,1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998,1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2010, 2011,2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023,2024, 2025, 2026, 2027, 2028, 2029, 2030, 2031, 2032, 2033, 2034, 2035,2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047,2048, 2049, 2050, 2051, 2052, 2053, 2054, 2055, 2056, 2057, 2058, 2059,2060, 2061, 2062, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2070, 2071,2072, 2073, 2074, 2075, 2076, 2077, 2078, 2079, 2080, 2081, 2082, 2083,2084, 2085, 2086, 2087, 2088, 2089, 2090, 2091, 2092, 2093, 2094, 2095,2096, 2097, 2098, 2099, 2100, 2101, 2102, 2103, 2104, 2105, 2106, 2107,2108, 2109, 2111, 2112, 2113, 2114, 2115, 2116, 2117, 2118, 2119, 2121,2122, 2123, 2124, 2125, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135,2136, 2137, 2138, 2139, 2140, 2143, 2144, 2145, 2146, 2147, 2148, 2149,2150, 2151, 2152, 2153, 2154, 2155, 2156, 2157, 2158, 2159, 2160, 2161,2162, 2163, 2164, 2166, 2167, 2168, 2169, 2170, 2171, 2172, 2173, 2174,2175, 2176, 2177, 2178, 2179, 2180, 2181, 2182, 2183, 2184, 2185, 2186,2187, 2188, 2189, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198,2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2207, 2208, 2209, 2210,2211, 2212, 2213, 2214, 2215, 2216, 2217, 2218, 2219, 2220, 2221, 2222,2223, 2224, 2225, 2226, 2227, 2228, 2229, 2230, 2231, 2232, 2233, 2234,2235, 2236, 2237, 2238, 2239, 2240, 2241, 2242, 2243, 2244, 2245, 2246,2247, 2248, 2249, 2250, 2251, 2252, 2253, 2254, 2255, 2256, 2257, 2258,2259, 2260, 2261, 2262, 2263, 2264, 2265, 2266, 2267, 2268, 2269, 2270,2271, 2272, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282,2283, 2284, 2285, 2286, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295,2296, 2297, 2298, 2299, 2300, 2302, 2303, 2304, 2305, 2306, 2307, 2308,2309, 2310, 2311, 2312, 2313, 2314, 2315, 2316, 2317, 2318, 2319, 2320,2321, 2322, 2323, 2324, 2325, 2326, 2327, 2328, 2329, 2330, 2331, 2332,2333, 2334, 2335, 2336, 2337, 2338, 2339, 2340, 2341, 2342, 2343, 2344,2345, 2346, 2347, 2348, 2349, 2350, 2351, 2352, 2353, 2354, 2355, 2356,2357, 2358, 2359, 2360, 2361, 2363, 2364, 2365, 2366, 2367, 2368, 2369,2370, 2371, 2372, 2373, 2374, 2375, 2376, 2377, 2378, 2379, 2380, 2381,2382, 2383, 2384, 2385, 2386, 2387, 2388, 2389, 2390, 2391, 2392, 2393,2394, 2395, 2396, 2397, 2398, 2399, 2400, 2401, 2402, 2403, 2404, 2405,2406, 2407, 2408, 2409, 2410, 2411, 2412, 2413, 2414, 2415, 2416, 2417,2418, 2419, 2420, 2421, 2422, 2423, 2424, 2425, 2426, 2427, 2428, 2429,2430, 2431, 2433, 2434, 2435, 2436, 2437, 2438, 2439, 2440, 2441, 2442,2443, 2444, 2445, 2446, 2447, 2448, 2449, 2450, 2451, 2452, 2453, 2454,2455, 2456, 2457, 2458, 2459, 2460, 2461, 2462, 2463, 2464, 2465, 2466,2467, 2468, 2469, 2470, 2471, 2472, 2473, 2474, 2475, 2476, 2477, 2478,2479, 2480, 2481, 2482, 2483, 2484, 2485, 2486, 2487, 2488, 2489, 2490,2491, 2492, 2493, 2494, 2495, 2496, 2497, 2498, 2505, 2506, 2509, 2510,2514.

Preferred combinations of A¹, A², G¹, A³, A⁴ and G² in the formula (I)were explained above. As another method of arrangement, they can besummarized also as the following combinations 1) through 41). Not onlydo these combinations indicate preferred relationships among A¹, A², G¹,A³, A⁴ and G², but also the partial structures per se comprised of theseas a whole are preferred substituents in the pyrrolopyrimidinonederivatives of the present invention.

1) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group asG¹ is preferably substituted with one or more substituents selected fromthose exemplified for the preferred substituents of the substitutedaromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

2) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, G¹ is a phenylene group, and the phenylene group asG¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is agroup other than a hydrogen atom.

3) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2, atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring.

4) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring. However,the divalent group derived from the aromatic heterocyclic compound as G¹is more preferably substituted with one or more substituents selectedfrom the group consisting of substituents defined as preferred examplesfor the heterocyclic compound having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring.

5) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring. However,when the divalent group derived from the aromatic heterocyclic compoundas G¹ is not substituted, it is more preferable that A³-A⁴-G² as a wholeis a group other than a hydrogen atom.

6) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is a acyclic aliphatic hydrocarbongroup having 1 to 6 carbon atoms or a cycloalkylalkyl group consistingof a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms andan alicyclic hydrocarbon group having 3 to 8 carbon atoms.

7) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² ispreferably a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms or a cycloalkylalkyl group consisting of a acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms and an alicyclichydrocarbon group having 3 to 8 carbon atoms as a whole, but a acyclicaliphatic hydrocarbon group having 1 to 6 carbon atoms as A³-A⁴-G² ismore preferably substituted with one or more substituents selected fromthose exemplified for the preferred substituents of the substitutedacyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³.Also, in a cycloalkylalkyl group consisting of a acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms and an alicyclichydrocarbon group having 3 to 8 carbon atoms as A³-A⁴-G², a acyclicaliphatic hydrocarbon group portion having 1 to 6 carbon atoms isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of the substitutedaliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or analicyclic hydrocarbon group portion having 3 to 8 carbon atoms isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of the substitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (includinga case where both are substituted).

8) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² ispreferably an aralkyl group consisting of a acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbongroup having 6 to 10 carbon atoms as a whole.

9) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² ispreferably an aralkyl group consisting of a acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbongroup having 6 to 10 carbon atoms as a whole, but in an aralkyl group asA³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6carbon atoms is further preferably substituted with one or moresubstituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon groupportion having 6 to 10 carbon atoms is further preferably substitutedwith one or more substituents selected from those exemplified for thepreferred substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms of G² (including a case where both aresubstituted).

10) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² ispreferably a heterocyclic substituted alkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and aheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering as a whole.

11) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² ispreferably a heterocyclic substituted alkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and aheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering as a whole. However, in the heterocyclic substituted alkyl group asA³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6carbon atoms is further preferably substituted with one or moresubstituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or a heterocyclic portion is furtherpreferably substituted with one or more substituents selected from thoseexemplified for the preferred substituents of the heterocyclic grouphaving 1 to 4 atoms selected from the group consisting of an oxygenatom, a nitrogen atom and a sulfur atom, in the ring, of G² (including acase where both are substituted).

12) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group asG¹ is preferably substituted with one or more substituents selected fromthose exemplified for the preferred substituents of the substitutedaromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

13) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene groupas G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is agroup other than a hydrogen atom.

14) In the formula (I), when A¹ is —(CH)₂— and A¹-A²-G¹ links in theform of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derivedfrom a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compoundhaving 1 to 3, preferably 1 or 2, atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering.

15) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derivedfrom a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compoundhaving 1 to 3, preferably 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering. However, the divalent group derived from the aromatic heterocycliccompound as G¹ is more preferably substituted with one or moresubstituents selected from the group consisting of substituents definedas preferred examples for the heterocyclic compound having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring.

16) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derivedfrom a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compoundhaving 1 to 3, preferably 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering. However, when the divalent group derived from the aromaticheterocyclic compound as G¹ is not substituted, it is more preferablethat A³-A⁴-G² as a whole is a group other than a hydrogen atom.

17) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is a cycloalkylalkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

18) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is a cycloalkylalkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatichydrocarbon group portion having 1 to 6 carbon atoms is more preferablysubstituted with one or more substituents selected from thoseexemplified for the preferred substituents of the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or analicyclic hydrocarbon group portion having 3 to 8 carbon atoms isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of the substitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (includinga case where both are substituted).

19) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is an aralkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and anaromatic hydrocarbon group having 6 to 10 carbon atoms.

20) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is an aralkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and anaromatic hydrocarbon group having 6 to 14 carbon atoms. However, in thearalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portionhaving 1 to 6 carbon atoms is more preferably substituted with one ormore substituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon groupportion having 6 to 10 carbon atoms is further preferably substitutedwith one or more substituents selected from those exemplified for thepreferred substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms of G² (including a case where both aresubstituted).

21) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferablethat A³-A⁴-G² as a whole is a heterocyclic substituted alkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and a heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring.

22) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferablethat A³-A⁴-G² as a whole is a heterocyclic substituted alkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and a heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring. However, in the heterocyclic substituted alkyl group asA³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6carbon atoms is further preferably substituted with one or moresubstituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or a heterocyclic group portion isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of theheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, of G² (including a case where both are substituted).

23) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH-G¹, and G¹ is a phenylene group, the phenylene group as G¹ ispreferably substituted with one or more substituents selected from thoseexemplified for the preferred substituents of the substituted aromatichydrocarbon group having 6 to 14 carbon atoms of G¹.

24) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ isnot substituted, it is preferable that A³-A⁴-G² as a whole is a groupother than a hydrogen atom.

25) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH-G¹, and G¹ is a divalent group derived from a monocyclic orbicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring, the aromatic heterocyclic group ispreferably substituted with one or more substituents selected from thegroup consisting of substituents defined as preferred examples for theheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering.

26) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-NH-G¹, G¹ is a divalent group derived from a monocyclic orbicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring, and the aromatic heterocyclic compoundis not substituted, it is more preferable that A³-A⁴-G² as a whole is agroup other than a hydrogen atom.

27) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-C(═O)-G¹, G¹ is preferably a divalent group derived from amonocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected fromthe group consisting of an oxygen atom, a nitrogen atom and a sulfuratom, in the ring, such as pyrrolidine, piperidine, morpholine,thiomorpholine, homopiperidine, homopiperazine,1,2,3,6-tetrahydropyridine or piperazine, and G¹ is bonded withA¹-C(═O)— through a nitrogen atom.

28) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from amonocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such aspyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine,homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ ispreferably bonded with A¹-C(═O)— through a nitrogen atom. However, thedivalent group derived from the monocyclic C₂-C₉ heterocyclic compoundhaving 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and asulfur atom, in the ring as G¹ is more preferably substituted with oneor more substituents selected from the group consisting of substituentsdefined as proffered examples for the heterocyclic group having 1 to 4atoms selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom on the substituted ring of G¹.

29) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in theform of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from amonocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected froman oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such aspyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine,homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ ispreferably bonded with A¹-C(═O)— through a nitrogen atom. However, whenthe divalent group derived from the monocyclic C₂-C₉ heterocycliccompound having 1 or 2 atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom, in the ring as G¹ is not substituted, it is morepreferable that A³-A⁴-G² as a whole is a group other than a hydrogenatom.

30) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ is a phenylene group, the phenylene group asG¹ is preferably substituted with one or more substituents selected fromthose exemplified for the preferred substituents of the substitutedaromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

31) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene group asG¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is agroup other than a hydrogen atom.

32) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in theform of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2, atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring.

33) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in theform of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring. However,the divalent group derived from the aromatic heterocyclic compound as G¹is more preferably substituted with one or more substituents selectedfrom the group consisting of substituents defined as preferred examplesfor the heterocyclic compound having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring.

34) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in theform of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from amonocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to3, preferably 1 or 2 atoms selected from the group consisting of anoxygen atom, a nitrogen atom and a sulfur atom, in the ring. However,when the divalent group derived from the aromatic heterocyclic compoundas G¹ is not substituted, it is more preferable that A³-A⁴-G² as a wholeis a group other than a hydrogen atom.

35) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is a cycloalkylalkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

36) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is a cycloalkylalkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatichydrocarbon group portion having 1 to 6 carbon atoms is more preferablysubstituted with one or more substituents selected from thoseexemplified for the preferred substituents of the substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or analicyclic hydrocarbon group portion having 3 to 8 carbon atoms isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of the substitutedalicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (includinga case where the both are substituted).

37) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is an aralkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and anaromatic hydrocarbon group having 6 to 14 carbon atoms.

38) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is morepreferable that A³-A⁴-G² as a whole is an aralkyl group consisting of aacyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and anaromatic hydrocarbon group having 6 to 10 carbon atoms. However, in thearalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portionhaving 1 to 6 carbon atoms is more preferably substituted with one ormore substituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon groupportion having 6 to 10 carbon atoms is further preferably substitutedwith one or more substituents selected from those exemplified for thepreferred substituents of the substituted aromatic hydrocarbon grouphaving 6 to 14 carbon atoms of G² (including a case where both aresubstituted).

39) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferablethat A³-A⁴-G² as a whole is a heterocyclic substituted alkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and a heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring.

40) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the formof A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferablethat A³-A⁴-G² as a whole is a heterocyclic substituted alkyl groupconsisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbonatoms and a heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring. However, in the heterocyclic substituted alkyl group asA³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6carbon atoms is further preferably substituted with one or moresubstituents selected from those exemplified for the preferredsubstituents of the substituted acyclic aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms of A³, or a heterocyclic group portion isfurther preferably substituted with one or more substituents selectedfrom those exemplified for the preferred substituents of theheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, of G² (including a case where both are substituted).

41) In the formula (I), when all of A¹, A², G¹, A³, and A⁴ represent asingle bond, G² is preferably a hydrogen atom or a acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms.

Also, the preferred combinations of X, A¹, A², G¹, A³, A⁴ and G² informula (I) as described in above 1) through 41) are more preferablycombined with a preferred group represented by R²-A⁵-, exemplified aspreferred combinations of R and A⁵, that is R²-A⁵- group in which A⁵ isa single bond and R² is a substituted or unsubstituted monocyclic C₃-C₅aromatic heterocyclic group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, in thering, or R²-A⁵- group in which R² is a substituted or unsubstitutedaliphatic hydrocarbon group, and with a preferred group represented byR³-A⁶-, exemplified as preferred combinations of R³ and A⁶.

The pyrrolopyrimidinone derivative of the formula (I) has tautomericforms represented by the following

[wherein A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same asthose defined above in the formula (I).]

However, needless to say all such tautomeric forms are within the scopeof the present invention.

When one or more asymmetric structures exist on atoms constitutingmolecules of the pyrrolopyrimidinone derivative formula (I), opticallyactive forms of the respective asymmetric structures and their mixturescombined in an arbitrary ratio are also within the scope of the presentinvention.

When there exist stereochemical isomers of molecules of thepyrrolopyrimidinone derivative of formula (I), the stereochemicalisomers and their combinations in any are also within the scope of thepresent invention.

The pyrrolopyrimidinone derivative of the formula (I) may have a basicgroup in its molecules. In this case, if necessary, it can be convertedinto pharmaceutically acceptable acid addition salts. Such acids includeinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, and carbonic acid; or organic acids such asacetic acid, citric acid, malic acid, oxalic acid, tartaric acid, lacticacid, maleic acid, fumaric acid, and methanesulfonic acid.

The pyrrolopyrimidinone derivative of formula (I) may have an acidicgroup in its molecules. In this case, when required, the acidic groupmay be converted into pharmaceutically acceptable salts, includingnon-toxic cation salts, exemplified by alkali metal ions such as Na⁺ orK⁺, alkaline earth metal ions such as Mg²⁺ or Ca²⁺, metal ions such asAl³⁺ or Zn²⁺, ammonia, and salts with an organic base such astriethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine,piperazine, pyridine, lysine, choline, ethanolamine,N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, orN-methylglucamine.

In the formula (II), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are thesame as those defined above in the formula (I), and examples thereofinclude the same as those exemplified in the formula (I), respectively.Also preferred examples of A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ andpreferred combinations of them are the same as those described for thepyrrolopyrimidinone derivative of the present invention represented inthe formula (I) except those being obstacle on the chemical reaction inboth of the reaction from the pyrrolopyrimidine derivative of thepresent invention represented by the formula (I) to thepyrrolopyrimidinone derivative of the present invention represented bythe formula (I), and the reaction from the pyrrolopyrimidine derivativerepresented by the formula (II) to the pyrrolopyrimidinone derivative ofthe present invention represented by the formula (I).

In the formula (II), X¹ represents a chlorine atom, a bromine atom, aniodine atom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, aC₁-C₈ alkyl group or a C₁-C₈ arylsulfonyloxy group, but an explanationwill be given below of the case where X¹ represents a chlorine atom, abromine atom, an iodine atom, or a C₁-C₈ alkyl or arylsulfonyloxy group.When X¹ represents a C₁-C₈ alkyl or arylsulfonyloxy group, examples ofthe C₁-C₈ alkyl or arylsulfonyloxy group include sulfonyloxy groupconsisting optionally substituted C₁-C₈ alkyl or aryl group and sulfonylgroup, such as methylsulfonyloxy, trifluoromethylsulfonyloxy,ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy,t-butylsulfonyloxy, nonafluorobutylsulfonyloxy, phenylsulfonyloxy,p-bromophenylsulfonyloxy, p-toluylsulfonyloxy, benzylsulfonyloxy,α-phenethylsulfonyloxy and β-phenethylsulfonyloxy. Examples of suchpreferred X¹ include a chlorine atom, a bromine atom, an iodine atom anda trifluoromethylsulfonyloxy group. Particularly, a chlorine atom or atrifluoromethylsulfonyloxy group is more preferred.

From the compounds represented by the formula (Ic), thepyrrolopyrimidinone derivative of formula (I) of the present inventioncan be easily manufactured based on the technical common sense of theperson skilled in the art.

In the formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are thesame as those defined above in formula (I), and examples thereof includethe same as those exemplified in formula (I), respectively.

In the formula (Ic), Q represents a C₂-C₁₀ acyl group, a C₂-C₁₀alkoxymethyl group, or a substituted or unsubstituted benzyl group. WhenQ represents a C₂-C₁₀ acyl group, examples of the C₂-C₁₀ acyl groupinclude acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl, phenylacetyl,phenylpropionyl, cinnamoyl. When Q represents a C₂-C₁₀ alkoxymethyl,examples of the C₂-C₁₀ alkoxymethyl group include methoxymethyl,methoxyethoxymethyl, t-butoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyl-oxymethyl,o-nitrobenzyloxymethyl and 4-methoxyphenoxymethyl. When Q represents asubstituted or unsubstituted benzyl group, examples of the substitutedor unsubstituted benzyl group include benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and p-cyanobenzyl.Examples of such preferred Q include 2-(trimethylsilyl)ethoxymethyl.

The pyrrolopyrimidinone derivative of the formula (I) can be preparedfrom pyrrolo[3,2-d]pyrimidine derivative of the formula (II) by thefollowing synthesis (A).

Note that, the pyrrolopyrimidinone derivative represented by the formula(I) is described as (Ia) in the following synthesis and is sometimesexpressed as a pyrrolo[3,2-d]pyrimidine derivative.

[wherein R^(1A) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² informula (I). R^(2A) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ informula (I). R^(3A) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R³-A⁶ informula (I). X¹⁰ represents a chlorine atom, a bromine atom, an iodineatom, or an optionally substituted C₁-C₈ alkyl or arylsulfonyloxygroup.]

In other words, the pyrrolopyrimidinone derivative Ia-A) of the presentinvention can be synthesized by hydrolysis of thepyrrolo[3,2-d]pyrimidine derivative (II-A). In this hydrolysis reaction,the reaction is performed by using a base such as a sodium hydroxide ora lithium hydroxide and using a solvent such as dioxane, ethanol,2-propanol, or dimethyl sulfoxide at a temperature in a range of 0° C.to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (II), apyrrolo[3,2-d]pyrimidine derivative of formula (II-B) can be synthesizedfrom the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia) by thefollowing synthesis.

[wherein R^(1B) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² informula (I). R^(2B) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ informula (I). R^(3B) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R³-A⁶ informula (I). X¹⁰ has the same meaning as defined above.]

In other words, when X¹⁰ is a chlorine atom, the pyrrolopyrimidinonederivative (II-B) of the present invention can be synthesized byreacting the pyrrolopyrimidinone derivative (Ia-B) of the presentinvention with phosphorus oxychloride. In the chlorination usingphosphorus oxychloride, the reaction is carried out in a solvent such asacetonitrile under general chlorination reaction conditions, forexample, in the presence or absence of a solvent such as triethylamine,4-dimethylaminopyridine or dimethyl type aniline, at a temperature in arange of 0° C. to 150° C.

Also, when X¹⁰ is a trifluoromethanesulfonyloxy group, thepyrrolopyrimidinone derivative (II-B) of the present invention can besynthesized by reacting the pyrrolopyrimidinone derivative (Ia-B) of thepresent invention with trifluoromethanesulfonic anhydride. Intrifluoromethane sulfonyloxylation using trifluoromethane sulfonicanhydride, the reaction can be carried out together with pyridine oramines such as triethylamine in the presence or absence of a solventsuch as dichloromethane at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), thepyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B1) can besynthesized from the 7-cyanopyrrolo[3,2-d]pyrimidine derivative of theformula (Ia-CN) by the following synthesis (B1).

[wherein R^(1B1) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B1) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B1) of thepresent invention can be synthesized by the hydrolyzingpyrrolo[3,2-d]pyrimidine derivative (Ia-CN). The hydrolysis reaction iscarried out using a base such as sodium hydroxide or lithium hydroxidein a solvent such as ethanol, 2-propanol or dimethylsulfoxide in thepresence or absence of hydrogen peroxide at a temperature in a range of0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-B2) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of the formula(Ia-B1) by the following synthesis (B2).

[wherein R^(1B2) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² informula (I). R^(2B2) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ informula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B2) of thepresent invention can be synthesized by performing a Hoffmannrearrangement on the pyrrolopyrimidinone derivative (Ia-B1) of thepresent invention. The Hoffmann rearrangement is carried out in asolvent such as ethanol, 2-propanol, acetonitrile or water, using areagent such as sodium hypochlorite, bromine, or benzyltrimethylammonium tribromide in the presence or absence of a base such as sodiumhydroxide at a temperature of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B3) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B2) by the following synthesis (B3).

[wherein R^(1B3) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B3) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I). R^(3B3) represents a fluorine atom, a chlorine atom, abromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B3) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Is-B2) of the present invention with nitrous acid or nitriteester and performing a Sandmayer reaction. In the Sandmayer reactionusing nitrous acid or nitrite ester, reagents, for example, nitrousacid, sodium nitrite, isoamyl nitrite, or t-butyl nitrite is used, andthe reaction can be performed in the presence of halogenation reagents,for example hydrofluoric acid or fluoroboric acid for fluorination, forexample copper chloride or carbon tetrachloride for chlorination, forexample carbon tetrabromide or bromoform for bromination, anddiiodomethane or iodine for iodination, in the presence or absence of anacid such as sulfuric acid or hydrochloric acid, in the presence orabsence of an acid such as sulfuric acid or hydrochloric acid, by usingor without using a solvent such as ethanol, acetonitrile or water, at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B4) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B2) by the following synthesis (B4).

[wherein R^(1B4) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B4) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B4) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-B2) of the present invention with nitrous acid or nitriteester. The reaction using nitrous acid or nitrite ester can be performedby using nitrous acid, sodium nitrite, isoamyl nitrite, or t-butylnitrite as a reagent, in the presence of or in the absence of an acidsuch as sulfuric acid or hydrochloric acid in the presence ofdimethylformamide, tetrahydrofuran, ethanol or water as a solvent, at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B5) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B4) by the following synthesis (B5).

[wherein R^(1B5) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B5) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B5) of thepresent invention can be synthesized by reacting nitric acid or nitrogendioxide with the pyrrolopyrimidinone derivative (Ia-B4) of the presentinvention. The reaction using nitric acid or nitrogen dioxide can beperformed by using nitric acid, nitrogen dioxide, cerium ammoniumnitrate or sodium nitrite as a reagent, in the presence or absence ofsulfuric acid, hydrochloric acid, acetic acid or ozone, in the presenceof dichloroethane, dichloromethane, acetonitrile or water as a solvent,at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B6) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B6a) by the following synthesis (B6).

[wherein R^(1B6) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B6) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I). R^(3B6a) is a bromine atom or iodine atom, and amonggroups defined as R³ in the formula (I), R^(3B6) is a substituted orunsubstituted saturated aliphatic hydrocarbon group having 1 to 10carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon grouphaving 3 to 8 carbon atoms, a substituted or unsubstituted aromatichydrocarbon group having 6 to 14 carbon atoms, a monocyclic C₃-C₅aromatic heterocyclic group having 1 or 2 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thesubstituted or unsubstituted ring, or a trimethylsilyl.]

In other words, the pyrrolopyrimidinone derivative (Ia-B6) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-B6a) of the present invention with a terminal alkynederivative represented by formula R^(3B6)—C≡C—H in the presence of acatalytic amount of palladium. The reaction with the terminal alkynederivative using the catalytic amount of palladium is carried out usingthe terminal alkyne derivative together with a palladium catalyst, e.g.,tetrakis(triphenylphosphine)palladium,chlorobis(triphenylphosphine)palladium, or palladium acetate, in thepresence or absence of a ligand, such as triphenylphosphine,tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in thepresence or absence of a catalytic amount of copper salts, e.g., copperiodide or copper bromide, in the presence of a base such astriethylamine, diethylamine, piperizine or pyrrolidine, using solventssuch as tetrahydrofuran, dimethylformamide, and toluene, at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B7) can be preparedfrom the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B7a) by thefollowing synthesis (B7).

[wherein R^(1B7) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B7) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I). R^(3B7a) is a bromine atom or an iodine atom. R^(3B7)is a substituted or unsubstituted aromatic hydrocarbon group having 6 to14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the substituted or unsubstituted ring among groupsdefined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B7) of thepresent invention can be synthesized, in the presence of a catalyticamount of palladium, by adding a boric acid derivative [R^(3B7)—B(OR)₂,wherein R^(3B7) is the same as defined above in the synthesis (B7), andR represents a hydrogen atom or an alkyl group] to thepyrrolopyrimidinone derivative (Ia-B7a) of the present invention. Thatis, in the reaction with the boric acid derivative using the catalyticamount of palladium, the reaction can be performed by using, togetherwith the boric acid derivative, a palladium catalyst, for example,chlorobis(triphenylphosphine)palladium, palladium acetate, andtris(dibenzylideneacetone)dipalladiumu-chloroform adduct in the presenceor absence of a ligand, such as triphenylphosphine,tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in thepresence of base such as potassium phosphate, sodium carbonate,potassium hydroxide, or sodium ethoxide, using a solvent such astetrahydrofuran, dimethylformamide, 2-propanol and water, at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B8) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ib-B8a) by the following synthesis (B8).

[wherein R^(1B8) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2B8) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I). R^(3B8a) is a bromine atom or an iodine atom, andR^(3B8) is a group defined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B8) of thepresent invention can be synthesized by reacting a terminal alkenederivative upon the pyrrolopyrimidinone derivative (Ia-B8a) of thepresent invention in the presence of a catalytic amount of palladium.That is, in the reaction with a terminal alkene derivative using thecatalytic amount of palladium, the reaction can be performed by using,together with the terminal alkene derivative, a palladium catalyst, forexample, palladium chloride, palladium acetate, ortris(dibenzylideneacetone)dipalladium-chloroform adduct in the presenceor absence of a ligand, such as triphenylphosphine,tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in thepresence of a base such as a potassium phosphate, potassium carbonate ortriethylamine, and using a solvent such as tetrahydrofuran,dimethylformamide or water, at a temperature in a range of 0° C. to 150°C.

Alternatively, the pyrrolopyrimidinone derivative (Ia-B8) of the presentinvention can also be synthesized by performing a catalyticsemi-reduction or hydroboration-protonation on thepyrrolo[3,2-d]pyrimidine derivative (Ia-B6) having an alkynyl groupprepared by the Synthesis (B6). For example, the catalyticsemi-reduction is performed using a solvent such as methanol, ethanol ortetrahydrofuran, in the presence of a palladium catalyst, e.g.,palladium-barium sulfate-quinoline, palladium-activatedcarbon-quinoline, under a hydrogen atmosphere, at a temperature in arange of 0° C. to 100° C. The hydroboration-protonation is performedsuch that hydroboratino is performed using a hydroborating reagent,e.g., 9-borabicyclo[3.3.1]nonane or dicyclohexylborane, and protonationis then performed using acetic acid. The reaction can be performed usinga solvent such as tetrahydrofuran, diethylether, methylenedichloride, ortoluene, at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B9) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B9a) by the following synthesis (B9).

[wherein R^(1B9) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² informula (I). R^(2B9) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ informula (I). R^(3B9a) is a bromine atom or an iodine atom. R^(3B9) is asubstituted or unsubstituted saturated aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms, substituted or unsubstituted C₁-C₁₀alicyclic hydrocarbon group, or a vinyl group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B9) of thepresent invention can be synthesized by reacting an organometallicreagent to the pyrrolopyrimidinone derivative (Ia-B9a) of the presentinvention using a catalytic amount of palladium or nickel. For example,in the reaction with the organometallic reagent using the catalyticamount of palladium or nickel, an organozinc reagent, e.g., phenylzincchloride or an organozinc compound prepared from a Grignard reagent andzinc chloride, an organotin reagent, e.g., phenyltrimethyltin ortetramethyltin can be used. As the Grignard reagent, organometallicreagents, such as phenylbromomagnesium or n-butylbromomagnesium, can beused. Useful examples of the palladium catalyst includetetrakis(triphenylphosphine)palladium,tris(dibenzylidene-acetone)dipalladium-chloroform adduct,chloro{1,1′-bis(diphenylphosphino)ferrocene}palladium, and the like.Useful examples of the nickel catalyst includechloro{1,3-bis(diphenylphosphino)propane}nickel or nickel bromide. Thereaction can be performed using a solvent such as diethylether,tetrahydrofuran or dimethylformamide, in the presence or absence of aligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or1,1′-bis(diphenylphosphino)ferrocene, at a temperature in a range of 0°C. to 150° C.

The pyrrolopyrimidinone derivative (Ia-B9) can also be synthesizedthrough hydrogen reduction of the pyrrolo[3,2-d]pyrimidine derivative(Ia-B6) having an alkynyl group prepared by the synthesis (B6) or thepyrrolo[3,2-d]pyrimidine derivative (Ia-B8) having an alkenyl groupprepared by the synthesis (B8). The hydrogen reduction is performedusing a solvent such as methanol, ethanol or tetrahydrofuran in thepresence of a catalytic amount of palladium-activated carbon under ahydrogen atmosphere at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B10) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Iz-10a) by the following synthesis (B10).

[wherein R^(1B10) represents a group capable of withstanding aconversion reaction among groups defined to be represented byA¹-A²-G¹-A³-A⁴-G² in the formula (I) R^(2B10) represents a group capableof withstanding a conversion reaction among groups defined to berepresented by R²-A⁵ in the formula (I). R^(3B10a) is a bromine atom oran iodine atom. R^(3B10) is a C₂-C₁₀ hydroxyl, alkoxy, N-substitutedamino or N,N-disubstituted amino group.

In other words, the pyrrolopyrimidinone derivative (Ia-B10) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-B10a) of the present invention with carbon monoxide inthe presence of a catalytic amount of palladium. For example, thecarbonyl insertion reaction using a catalytic amount of palladium isperformed under a carbon monoxide atmosphere, using a palladiumcatalyst, e.g., tetrakis(triphenylphosphine)palladium, palladiumacetate, or tris(dibenzylideneacetone)dipalladium-chloroform adduct, inthe presence or absence of a ligand, e.g., triphenylphosphine,tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in thepresence or absence of a base, e.g., potassium carbonate, ortriethylamine. A solvent such as acetonitrile, tetrahydrofuran, ordimethylformamide is used, and the reaction is carried out at atemperature ranging between 0° C. and 150° C. In this case, addition ofwater as a reacting agent gives a compound with a carboxy group, andaddition of an alcohol gives a compound with an alkoxycarbonyl group.Addition of a primary or secondary amine gives a compound withN-substituted or N,N-disubstituted aminocarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B11) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-11a) by the following synthesis (B11).

[wherein R^(1B11) represents a group capable of withstanding aconversion reaction among groups defined to be represented byA¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B11) represents a groupcapable of withstanding a conversion reaction among groups defined to berepresented by R²-A⁵ in the formula (I). R^(2B11a) is a bromine atom oran iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B11) of thepresent invention can be synthesized by reacting thepyrrolo[3,2-d]pyrimidine derivative (Ia-B11a) of the present inventionunder a carbon monoxide atmosphere in the presence of a reducing agentand a catalytic amount of palladium. For example, the formylationreaction using a catalytic amount of palladium is performed under thecarbon monoxide atmosphere. Useful examples of the palladium catalystinclude tetrakis(triphenylphosphine)palladium, palladium acetate,tris(dibenzylideneacetone)dipalladium-chloroform adduct. The reaction isperformed using a solvent such as acetonitrile, tetrahydrofuran, ordimethylformamide in the presence or absence of a ligand such astriphenylphosphine or tri(o-tolyl)phosphine or1,1′-bis(diphenylphosphino)ferrocene in a temperature range of 0° C. to150° C. The reaction is performed in the presence of or in the absenceof a base such as potassium carbonate or triethylamine. Addition of areducing agent such as tributyltin hydride or triethylsilane gives acompound with a formyl group, and addition of an organometallic agentsuch as alkyl zinc, alkyl boron or an organotin reagent give a compoundwith an alkylcarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B12) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B12a) by the following synthesis (B12).

[wherein R^(1B12) represents a group capable of withstanding aconversion reaction among groups defined to be represented byA¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B12) represents a groupcapable of withstanding a conversion reaction among groups defined to berepresented by R²-A⁵ in the formula (I). R^(3B12a) is a bromine atom oran iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B12) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-B12a) of the present invention with a trifluoromethyldonating reagent. That is, in the trifluoromethylation reaction, thereaction can be performed by utilizing various methods, for example, amethod using copper (I) iodide or cesium fluoride together with atrifluoromethyl donator such as sodium trifluoroacetate ortrifluoromethyl acetate, a method for preparing a trifluoromethyl coppercompound from a trifluoromethyl zinc compound or a trifluoromethylcadmium compound and copper (I) bromide, or a method for preparing atrifluoromethyl copper compound from a trifluoromethyl iodide and copperpowder, by using a solvent such as dimethylformamide,N-methylpyrrolidinone, hexamethylphosphoramide, acetonitrile, orpyridine, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of Formula (Ia-B13) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of Formula(Ia-B13a) by the following synthesis (B13).

[wherein R^(1B13) represents a group capable of withstanding aconversion reaction among groups defined to be represented byA¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B13) represents a groupcapable of withstanding a conversion reaction among groups defined to berepresented by R²-A⁵ in the formula (I).]

The pyrrolopyrimidinone derivative (Ia-B13) of the present invention canbe synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B13a)of the present invention with water in the presence of nitrous acid.That is, the hydroxylation reaction in the presence of nitrous acid isperformed using sodium nitrite or isoamyl nitrite in the presence oftrifluoroacetic acid or sulfuric acid. The reaction can be performedusing water as a solvent in the presence or absence of a cosolvent suchas acetonitrile or dimethylformamide, at a temperature in a range of 0°C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B14) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-B14a) by the following synthesis (B14).

[wherein R^(1B14) represents a group capable of withstanding aconversion reaction among groups defined to be represented byA¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B14) represents a groupcapable of withstanding a conversion reaction among groups defined to berepresented by R²-A⁵ in the formula (I). R^(3B14) is a C₁-C₆ aliphatichydrocarbon group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B14) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-B14a) of the present invention with water in the presenceof nitrous acid. That is, the alkylthioration reaction in the presenceof nitrous acid is performed using sodium nitrite or isoamyl nitrite inthe presence or absence of acids such as hydrochloric acid or sulfuricacid. The reaction is carried out using dialkyldisulfide or alkanethiolas a reagent in a solvent such as acetonitrile or dimethylformamide at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by (Ia-B) ofthe synthesis (B) or (Ib-CN) of the synthesis (B1), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-C2) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-C1) by the following synthesis (C).

[wherein R^(1C) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2C1) is a chlorine atom or a bromine atom. R^(3C)represents a cyano group or a group capable of withstanding a conversionreaction among groups defined to be represented by R²-A⁵ in the formula(I). When A⁵ is —NR²⁰¹— (R²⁰¹ is the same as defined above for R²⁰¹ inthe formula (1)), R^(2C2) is as defined to exclude a fluorine atom, achlorine atom, a bromine atom and an iodine atom from groups defined forR² in formula (I). Also, when A⁵ is a single bond, R^(2C2) is aheterocyclic group having 1 to 4 atoms selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom on thesubstituted or unsubstituted ring in which R^(2C2) is linked to A⁵ on anitrogen atom.

In other words, the pyrrolopyrimidinone derivatives (Ia-C2) can besynthesized by reacting the pyrrolopyrimidinone derivatives (Ia-C1) ofthe present invention with a primary or secondary amine. Amination usingthe primary or secondary amine is performed without the use of a solventor with the use of a solvent such as dimethylsulfoxide,dimethylformamide, dioxane, tetrahydrofuran or toluene in the presenceor absence of a base such as pyridine, triethylamine,diisopropylethyl-amine, 4-dimethylaminopyridine or sodium carbonate. Thereaction is performed in the presence or absence of a transition metalcomplex catalyst prepared by mixing a palladium salt such as palladiumacetate with a phosphorus ligand such as triphenylphosphine, at atemperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by theformula (Ia) or (Ia-CN) of the synthesis (B1), apyrrolo[3,2-d]pyrimidine derivative of formula (Ia-D2) can besynthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula(Ia-D1) by the following synthesis (D).

[wherein R^(1D) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2D1) is a chlorine atom or a bromine atom. R^(2D2)is a substituted or unsubstituted aromatic hydrocarbon group having 6 to14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom on the substituted or unsubstituted ring. R^(3D) is acyano group or a group capable of withstanding a conversion reactionamong groups defined to be represented A⁶-R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-D2) of thepresent invention can be synthesized by reacting the pyrrolopyrimidinonederivative (Ia-D1) of the present invention with, for example, a boricacid derivative represented by R^(2D2)—B(OR)₂ [in which R^(2D2) is asdefined above in the synthesis (D), and R is a hydrogen atom or an alkylgroup]. The reaction with the boric acid derivative is performed undergeneral Suzuki reaction conditions, for example, at a temperature in arange of 0° C. to 150° C. using a solvent such as 2-propanol and/orwater in the presence of an inorganic base such as sodium carbonate, byusing a catalyst such as palladium acetate, and adding a ligand such astriphenylphosphine.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or(Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidinederivative of formula (Ia-E2) can be synthesized from thepyrrolo[3,2-d]pyrimidine derivative of formula (Ia-E1) in the followingmanner shown in Synthesis (E):

[wherein R^(1E) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2E) is a chlorine atom, a bromine atom or an iodineatom. R^(3E) is a cyano group or a group capable of withstanding aconversion reaction among groups defined to be represented by A⁶-R³.]

In other words, the pyrrolopyrimidinone derivative (Ia-E2) of thepresent invention can be synthesized by halogenation of thepyrrolopyrimidinone derivative (Ia-E1) of the present invention. Thehalogenation is performed using a halogenation reagent such asN-chlorosuccinic imide or N-bromosuccinic imide in the presence of asolvent such as dimethylformamide, dioxane or tetrahydrofuran at atemperature in a range of −20° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or(Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidinederivative of formula (1a-F) given below can be synthesized from thepyrrol derivative of formula (IV-F) in the following manner shown inSynthesis (F):

[wherein R^(1F) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2F) represents, among the groups defined for R² inthe formula (I), groups excluding a fluorine atom, a chlorine atom, abromine atom, an iodine atom, and a substituted or unsubstitutedheterocyclic group that is bonded with a carbon atom and a nitrogen atomof a pyrrole ring to which R^(2F) is bonded, and having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring. R^(3F) is a cyano group or a groupcapable of withstanding a conversion reaction among groups defined to berepresented by A⁶-R³ in formula (I).]

In other words, the pyrrolo[3,2-d]pyrimidine derivative of the formula(Ia-F) of the present invention can be synthesized by performing acyclization reaction using formamidine or formamide on the pyrrolederivative of formula (IV-F). The cyclization reaction using formamidinecan be performed by using formamidine acetate, for example, in a solventsuch as 2-propanol at a temperature in a range of 0° C. to 150° C. Thecyclization reaction using formamide can be performed smoothly by usinga base such as formamide or sodiummethoxide, in the presence or absenceof a solvent such as dimethylsulfoxide or dimethoxyethane at atemperature in a range of 0° C. to 150° C.

The pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia) or thesynthesis (B1) can be synthesized from the pyrrolo[3,2-d]pyrimidinederivative of the Formula (I-G) by the following synthesis (G).

[wherein R^(1G) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2G) represents a group capable of withstanding aconversion reaction among groups defined to be represented by R²-A⁵ inthe formula (I). R^(3G) is a cyano group or a group capable ofwithstanding a conversion reaction among groups defined to berepresented by A⁶-R³ in formula (I). Q is an optionally substitutedC₂-C₁₀ acyl group, an optionally substituted a C₂-C₈ alkoxymethyl group,or substituted or unsubstituted benzy group.]

In other words, when for example Q is an acyl group, thepyrrolopyrimidinone derivative (Ib-G) of the present invention can besynthesized by reacting the pyrrolopyrimidinone derivative (I-G) of thepresent invention with an acyl halide. The acylation reaction using theacyl halide is performed under conventional acylation reactionconditions, for example, in the presence of triethylamine or pyridine,at a temperature in a range of 0° C. to 100° C.

Also, when Q is for example an alkoxymethyl or benzyl group, thepyrrolopyrimidinone derivative (I-G) of the present invention can besynthesized by reacting the pyrrolo[3,2-d]pyrimidine derivative (I-G) ofthe present invention with an alkoxymethyl halide or a benzyl halide.The reaction using the alkoxymethyl halide or the benzyl halide can beperformed in the presence of for example sodium hydride in a temperaturerange of 0° C. to 100° C.

In the thus obtained pyrrolopyrimidinone derivatives (Ib-G) according tothe present invention, conversion reactions known to one skilled in theart can be performed for A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and/or R³.Such pyrrolo[3,2-d]pyrimidine derivatives (Ib-G) can be converted intothe pyrrolopyrimidinone derivatives (I-G) of the present invention byperforming hydrolysis under a neutral or alkaline condition when Q is anacyl group, or under an acidic condition using, for example,trifluoroacetic acid, when Q is an alkoxymethyl group, or by performinga hydrogen addition reaction when R³ is a benzyl group.

The pyrrolopyrimidinone derivatives or the present invention synthesizedby the syntheses (A), (B), (C), (D), (E), (F), and (G) have easilyconvertible substituents, such as an alkoxycarbonyl group, an acyloxygroup, or an aromatic nitro group, they can be easily converted intopyrrolopyrimidinone derivatives or the present invention respectivelyhaving a carboxy group, a hydroxy group, and an amino group byperforming reactions known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present inventionsynthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) havea carboxy group, they can be converted into pyrrolopyrimidinonederivatives of the present invention having an alkoxycarbonyl group, acarbamoyl group, and an N-alkylcarbamoyl group by a condensationreaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the synthesized by thesynthesis (A), (B), (C), (D), (E), (F), and (G) have an amino group,they can be converted into pyrrolopyrimidinone derivatives of thepresent invention having an acylamino group or an alkylsulfonylaminogroup by a condensation reaction well known to one skilled in the art.

Also, when they have an amino group, they can also be converted intopyrrolopyrimidinone derivatives of the present invention having amonoalkylamino or a dialkylamino group by a reductive alkylationreaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present inventionsynthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) havea hydroxy group, they can be converted into pyrrolopyrimidinonederivatives of the present invention having an acyloxy group by acondensation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present inventionsynthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) havea formyl group, they can be converted into pyrrolopyrimidinonederivatives of the present invention having an alkylaminomethyl group bya reductive alkylation reaction known to one skilled in the art.

In the synthesis of the pyrrolopyrimidinone derivative of the formula(I), the pyrrole derivatives of formula (IV-F) used as startingmaterials can be prepared from a 3-alkoxypropene nitrile derivative offormula (VI-H) by the following synthesis (H).

[wherein R^(1H) represents a group capable of withstanding a conversionreaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² inthe formula (I). R^(2H) represents, among the groups defined for R²-A⁵in the formula (I), groups excluding a fluorine atom, a chlorine atom, abromine atom, an iodine atom, and a substituted or unsubstitutedheterocyclic group that is bonded with a carbon atom and a nitrogen atomof a pyrrole ring to which R^(2H) is bonded, and having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring. R^(3H) is a cyano group or a groupcapable of withstanding a conversion reaction among groups defined to berepresented by A⁶-R³ in formula (I).]

In other words, aminopropenitrile derivatives (V-H) can by synthesizedby reacting alkoxypropene nitriles (VI-H) with a primary amine(represented by R¹—NH₂ in which R¹ is as defined above for R¹ preparedby the synthesis (H)). The pyrrole derivatives (IV-H) can be synthesizedthrough a reaction between the aminopropenenitrile derivatives (V-H) andmethyl bromoacetate in the presence of a base, or through a cyclizationreaction.

The reaction between the alkoxypropene nitrile derivatives (V-H) and theprimary amine is performed using a solvent such as methanol, ethanol or2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the alkoxypropenenitrile derivatives (VI-H) andmethyl bromoacetate is performed in the presence of a base such assodium carbonate using a solvent such as acetonitrile at a temperaturein a range of 0° C. to 150° C.

In the synthesis of the pyrrolopyrimidinone derivative of the formula(I), among the pyrrole derivatives of the formula (IV-F) used asstarting materials, a pyrrole derivative having a hydrogen atom asR^(2F) can be prepared from 3-oxopropanenitrile derivatives of formula(VII-J) by the following synthesis (J)

[wherein R^(1J) represents a group which can be converted toA¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable ofwithstanding a conversion reaction. R^(3J) is a cyano group or a groupcapable of withstanding a conversion reaction among groups defined to berepresented by A⁶-R³ in the formula (I).]

In other words, the aminopropenenitrile derivative (V-J) can besynthesized by reacting the 3-oxopropanenitrile derivative (VII-J) witha primary amine (R¹—NH₂ in which R¹ is as defined above for R¹ preparedby the synthesis (J)). The pyrrole derivatives (IV-J) can be synthesizedthrough a reaction between the aminopropenitrile derivatives (V-J) andmethyl bromoacetate in the presence of a base, or through a cyclizationreaction.

The reaction between 3-oxopropanenitrile derivative (VII-J) and theprimary amine is performed using a solvent such as methanol, ethanol or2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the aminopropenitrile derivative (VI-J) and methylbromoacetate is performed in the presence of a base such as sodiumcarbonate using a solvent such as acetonitrile in a temperature range of0° C. to 150° C.

Alternatively, in the syntheses of the pyrrolopyrimidinone derivative ofthe formula (I), among the pyrrole derivatives of formula (IV-F) used asstarting materials, a pyrrole derivative of formula (IV-F) having ahydrogen atom as R²F can also be prepared by the following synthesis(K):

[wherein R^(1K) represents a group which can be converted toA¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable ofwithstanding a conversion reaction. R^(3K) is a cyano or a group capableof withstanding a conversion reaction among groups defined to berepresented by A⁶-R³ in formula (I).]

In other words, the aminopropenitrile derivative (V-K) can bysynthesized by reacting the 3-oxopropanenitrile derivative (VII-K) and aglycinemethylester derivative (R¹—NH—CH₂—COOCH₃ having R¹ on a nitrogenatom in which R¹ is as defined above for R¹ prepared by the synthesis(K)) The pyrrole derivative (IV-L) can be synthesized by performingcyclization of the aminopropenitrile derivative (V-K) in the presence ofa base.

The reaction between the 3-oxopropanenitrile derivative (VII-K) and theglycinemethylester derivative is performed using a solvent such asacetic acid at a temperature in a range of 0° C. to 150° C.

The cyclization reaction of the aminopropenitrile derivative (V-K) isperformed using a solvent such as acetonitrile or ethylene glycoldimethyl ether in the presence of a base such as1,8-diazabicyclo[5,4,0]-7-undecene or cesium carbonate at a temperaturein a range of 0° C. to 150° C.

The thus obtained pyrrolopyrimidinone derivatives of formula (I) have aninhibitory effect of GSK-3 activity, and can be advantageously used aspreventive and/or therapeutic agents which are clinically applicableGSK-3 inhibitors. Diseases that can be treated by the GSK-3 activityinhibitor include diabetes, diabetic complications, atherosclerosis,hypertension, obesity, syndrome X, Alzheimer's disease,neurodegenerative diseases (AIDS encephalophy, Huntington's disease,Parkinson's disease, or ischemic attack), manic depressive psychosis,traumatic cerebrospinal injury, alopecia, inflammatory responsesyndrome, cancer and immunodeficiency.

Also, the pyrrolopyrimidinone derivatives of formula (I) and itspharmaceutically acceptable salts may be formed as pharmaceuticalcompositions together with pharmacologically acceptable carriers and/ordiluents. The compositions of the present invention may be formed asvarious kinds of formulations to be administered orally or parenterally.The term “parenteral” as used herein includes intravenous, subcutaneous,intramuscular, percutaneous, and rectal injection or infusiontechniques.

For oral administration, examples of the formulation include tablets,pills, granules, powder, solutions, suspensions, syrups, and so on.

Here, the tablet formulations can be formed by conventional methodsusing a pharmaceutically acceptable carrier such as a vehicle, a bindingagent, a disintegrating agent, and the like. The pills, granules andpowder can also be formed by conventional methods using a vehicle or thelike, like the tablets. The formulations in the form of solutions,suspensions and syrups can be prepared by general methods usingglycerine esters, alcohols, water, vegetable oils, and so on. Thecapsule formulations can be formed by filling capsules of gelatin withgranules, powder or solutions.

Among formulations for parenteral administration, intravenous,subcutaneous, and intramuscular administration can take forms ofinjectable formulations. For injection, the compounds of the inventionmay be formulated in aqueous solutions such as physiological saline orin nonaqueous solutions including organic esters such as propyleneglycol, polyethylene glycol, or vegetable oils.

For transdermal administration, formulations can be used in the form ofointment or cream. Ointments can be used in combination with oils orvaselin, for example. Creams can be prepared in combination withemulsifying agents, for example.

When required, these formulations can be further provided withpharmaceutically acceptable carriers such as an isotonic, apreservative, an antiseptic, a wetting agent, a buffering agent, anemulsifying agent, a dispersing agent, or a stabilizer.

Also, such a variety of formulations can be sterilized throughappropriate treatments, for example, filtration using a bacteriaretaining filter or combination of disinfectants.

The amount of the pyrrolopyrimidinone derivative of formula (I) and itspharmaceutically acceptable salt that may be administered may varydepending upon the kind of a disease, administration route, symptom,age, sex, body weight, and so on of the patient. Generally, a dosage fororal administration is between 0.1 and 500 mg/day/patient. A dosage forparenteral application, including intravenous, subcutaneous,intramuscular, and percutaneous injection is between 0.1 and 100mg/day/patient.

EXAMPLES

The present invention will now be described in more detail through thefollowing examples. However, the present invention is not limited tothese examples. In the following examples, compound numbers labeled forthe respective compounds correspond to the compound numbers labeled forthe compounds listed in the above tables as specific examples.

Note that, with regard to data for compounds synthesized in thefollowing examples, the term “HPLC retention time” refers to a retentiontime (unit: min) associated with a particular compound in HPLC analysisperformed under the following analysis condition. HPLC (High performanceliquid chromatography) Analysis Condition

-   System: Hewlett-Packard 1100 HPLC-   Column: Cadenza CD-C18 (manufactured by Imtakt Co.) 100 mm×4.6 mmφ    Solvent A:

H₂O/acetonitrile=95/5 (0.05% trifluoroacetic acid)

Solvent B:

H₂O/acetonitrile=5/95 (0.05% trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0 to 1 min Solvent B: 10%, Solvent A: 90%

1 to 14 min Solvent B: 10% →100%, Solvent A: 90% →0%

14 to 16 min Solvent B: 100%, Solvent A: 0% Calculation of the purity:Area percentage at UV absorption (254 nm)

Reference Example 1 Synthesis of(cyclopropylhydroxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (150 mL) suspension of sodium hydride (11.49 g) wascooled to 0° C. To the cooled suspension was added dropwise atetrahydrofuran (50 mL) solution of malononitrile (15.8 g) over an hour.The reaction mixture was stirred at room temperature for 1 hour andcooled to 0° C. To the reaction mixture was added dropwise over 80minutes a tetrahydrofuran (50 mL) solution of cyclopropylcarbonylchloride (25.0 g). The reaction mixture was stirred at room temperaturefor 49 hours, followed by adding water (50 mL) to the reaction solution.The solvent was distilled off under reduced pressure. To the residuewere added ethyl acetate (200 mL) and hydrochloric acid (270 mL, 1mol/L), which was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate, andthen the solvent was distilled off under reduced pressure to obtain acrude product (40.9 g) of the title compound. The NMR data of thecompound is given below.

¹H-NMR (400 MHz, CDCl₃)δ(ppm): 1.10-1.22 (m, 4H), 2.10-2.22 (m, 1H),4.27 (s, 3H).

In a similar manner as described above,[(3-chloro(2-thienyl))hydroxymethylene]methane-1,1-dicarbonitrile wasprepared from malononitrile and 3-chlorothiophene-2-carbonylchloride.The NMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, CD₃OD) δ(ppm): 6.92 (d, J=5.1, 1H) 7.51 (d, J=5.4, 1H)ESI/MS m/e: (M⁺+H, C₈H₃ClN₂OS).

Reference Example 2 Synthesis of(cyclopropylmethoxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (100 mL) suspension of sodium hydride (2.6 g) wascooled to 0° C. To the cooled suspension was added dropwise atetrahydrofuran (60 mL) solution of crude(1-hydroxy-2-phenylmethylidene)methane-1,1-dicarbonitrile (14.5 g) over30 minutes. The reaction mixture was stirred at room temperature for 20minutes and cooled to 0° C. To the reaction mixture was added dropwise atetrahydrofuran solution (40 mL) of dimethyl sulfate (13.7 g) over 1hour. After heating for 21 hours to reflux, the reaction mixture wascooled to room temperature, and the solvent was distilled off underreduced pressure. To the residue were added ethyl acetate (100 mL) andsaturated sodium hydrogen carbonate solution (100 mL), and extractionwith ethyl acetate was performed. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, and then thesolvent was distilled off under reduced pressure. The obtained crudeproduct was purified by column chromatography on silica gel usinghexane/ethyl acetate=1/3 as an eluent to obtain the title compound (6.8g, 54%) as a light yellow solid. NMR data of the compound is givenbelow.

¹H-NMR (400 MHz, CDCl₃)δ(ppm): 1.10-1.22 (m, 4H), 2.10-2.22 (m, 1H),4.27 (s, 3H).

Reference Example 3 Synthesis of methyl3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate

To an acetonitrile (150 mL) solution of(methoxycyclopropylmethylene)methane-1,1-dicarbonitrile (8.7 g) wasadded N-(2-aminoethyl) t-butyl carbaminic acid (16.3 g) and stirred atroom temperature for 10 minutes. To the resultant product were addedanhydrous cesium carbonate (38.5 g) and methyl bromoaccetate (11.2 mL),followed by heating for 6 hours to reflux. The reaction product wascooled to room temperature and allowed to stand. Then, the supernatantwas separated by decantation and the solvent was distilled off underreduced pressure. The concentrated residue and a solid remaining afterdecantation were collected and ethyl acetate and water were addedthereto, followed by extracting 3 times with ethyl acetate. The organicphase was washed with water and saturated brine, and dried overanhydrous magnesium sulfate. After magnesium sulfate was removed byfiltration, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=2/1) to obtain the title compound (17.5 g, yield85%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 349.1 (M⁺+H, C₁₇H₂₄N₄O₄)

Methyl3-amino-1-{2-[(t-butoxy)carbonylamino}ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylatewas synthesized from[(3-chloro(2-thienyl))hydroxymethylene]methane-1,1-dicarbonitrile usedas a starting material in a similar manner to that in Reference Examples2 and 3. The ESI/MS data of the compound are given below.

ESI/MS m/e: 425.2 (M⁺+H, C₁₈H₂₁ClN₄O₄S)

Reference Example 4 Synthesis of(t-butoxy)-N-[2-(7-cyano-4-oxo-6-cyclopropyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))ethyl]carboxyamide

Methyl3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate(17.4 g) and formamidine acetate (104.1 g) were added to 2-propanol (360mL) and heated for 45 hours to reflux. The reaction mixture was cooledto room temperature, and the solvent was distilled off under reducedpressure. To the residue was added water, and the obtained solid wasisolated by filtration and sufficiently washed with water. The resultingsolid was recrystallized (ethanol/ethyl acetate/hexane=1/2/1) to obtainthe title compound (9.8 g, yield 57%). The ESI/MS data of the compoundare given below.

ESI/MS m/e: 362.1 (M⁺+H, C₁₇H₂₁N₅O₃)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamidewas prepared frommethyl-3-amino-1-{2-[(t-butoxy)carbonyl-amino]ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylatein a similar manner to that described above. ESI/MS data of the compoundare given below.

ESI/MS m/e: 420.2 (M⁺+H, C₁₈H₁₈ClN₅O₃S)

Reference Example 5 Synthesis of 3-oxo-2-(3-pyridyl)propanenitrilehydrochloride

To a toluene solution (100 mL) of 3-pyridylacetonitrile (40.86 g) wasadded dimethylformamidedimethylacetal (123.6 g) and the mixture washeated for 4 hours to reflux. The reaction solution was cooled to roomtemperature, and the solvent was distilled off under reduced pressure.The residue was purified by column chromatography on silica gel (ethylacetate) to obtain a brown solid. The obtained brown solid was washedwith ethyl acetate, yielding 46.93 g of a colorless solid. To atetrahydrofuran (300 mL) suspension of the reaction product (20.37 g)were added water (40 mL) and concentrated hydrochloric acid (24.50 mL)and the mixture was stirred at 50° C. for 4 hours. The reaction solutionwas cooled to room temperature, and the solvent was distilled off underreduced pressure. The residue was dried in vacuo to obtain a crudeproduct (30.12 g) of the title compound, which was used for thesubsequent reaction without further purification. ESI/MS data of thecompound are given below.

ESI/MS m/e: 147.1 (M⁺+H, C₈H₆N₂O HCl)

Reference Example 6 Synthesis of ethyl3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate

To an acetic acid (30 mL) solution of ethyl3-{[(methoxycarbonyl)methyl]amino}propanate (6.720 g) was added a crudeproduct of 3-oxo-2-(3-pyridyl)propanenitrile (7.826 g), and the mixturewas stirred at 80° C. for 2 days. The reaction solution was cooled toroom temperature, and the solvent was distilled off under reducedpressure. The residue was diluted with water, and sodium carbonate wasadded thereto for neutralization, followed by extracting the solutionwith ethyl acetate. The organic layer was washed with saturated brine,and dried over sodium sulfate, which was then filtered for separation.Thereafter, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=1/3), to obtain the title compound (7.521 g, yield83%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 318.2 (M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 7

Synthesis of ethyl3-[3-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl]propanate

To an ethylene glycol dimethyl ether (50 mL) solution of ethyl3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate(6.236 g) was added 1,8-diazabicyclo[5,4,0]-7-undecene (3.590 g), andthe mixture was stirred at 60° C. overnight. The reaction solution wascooled to room temperature and neutralized with acetic acid, and thesolvent was distilled off under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=1/5), to obtain the title compound (4.380 g, yield 70%). The NMRdata and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.10-1.18 (m, 3H), 2.74 (t, J=6.82,2H), 3.77 (s, 3H), 3.99-4.07 (m, 2H), 4.38 (t, J=6.84, 2H), 7.46 (s,1H), 7.85 (dd, J=5.74, J=7.94, 1H), 8.36 (d, J=8.08, 1H), 8.60 (d,J=5.40, 1H), 8.84 (s, 1H). ESI/MS m/e: 318.2 (M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 8 Synthesis of(cyclopropylhydroxy-methylene)methane-1-(3-pyridyl)-1-carbonitrile

To a 500 mL branched flask was added 13.0 g of 3-pyridinacetonitrile(110 mmol) and 150 mL of tetrahydrofuran, and 44 mL of ^(n)BuLi (2.6 Msolution) (114 mmol) was added dropwise thereto using a syringe withstirring at 0° C., followed by stirring at 0° C. for 30 minutes and at40° C. for 30 minutes. While the reaction product was cooled at 0° C.with stirring, a tetrahydrofuran solution (30 mL) of 10.45 g ofcyclopropanecarbonyl chloride (100 mmol) was added dropwise, and stirredat room temperature for 1 hour, followed by adding to the reactionsolution 300 mL of a saturated ammonium chloride solution and separated.The aqueous layer was extracted with 100 mL of ethyl acetate. Theorganic layer was washed twice with 300 mL of saturated brine. Theorganic layer was dehydrated and dried over magnesium sulfate, filteredand concentrated to obtain 18.25 g of concentrated residue. To theconcentrated residue was added 30 mL of acetonitrile and an insolubleportion was filtered off, followed by washing with 20 mL of acetonitrileto obtain a crude product of the title compound (5.17 g, 28%). The NMRdata and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.64 (m, 4H), 2.24 (m, 1H) 2.50 (brds,1H), 7.70 (dd, J=5.4 Hz, J=8.6 Hz, 1H), 8.11 (d, J=5.4 Hz, 1H), 8.21 (d,J=8.6 Hz, 1H), 9.12 (brds, 1H). ESI/MS m/e: 187.1 (M⁺+H, C₁₁H₁₀N₂O).

Reference Example 9 Synthesis of(cyclopropyl-p-toluene-sulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile

A 200 mL branched flask were charged with 4.51 g of(cyclopropylhydroxymethylene)methane-1-(3-pyridyl)-1-carbonitrile (24.3mmol) and 9.14 g of p-toluene sulfonic anhydride (28 mmol), and 100 mLof dichloromethane was added thereto, followed by adding 4.8 mL oftriethylamine (34.5 mmol) dropwise with stirring the reaction mixture atroom temperature, and stirring at room temperature for 2 hours. Afterthe completion of the reaction, 50 mL of water was added to the reactionsolution and separated. The aqueous layer was extracted with 20 mL ofdichloromethane. The organic layer was washed once with 50 mL ofsaturated sodium hydrogen carbonate solution and twice with 50 mL ofwater. The organic layer was dehydrated and dried over magnesiumsulfate, filtered and concentrated to obtain a crude product (8.47 g,100%) of the title compound. The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.10-1.32 (m, 4H), 2.40 (s, 3H) 2.15-2.42(m, 1H), 7.05 (m, 3H), 7.40 (m, 2H), 7.60 (m, 1H), 8.40 (m, 2H). ESI/MSm/e: 341.0 (M⁺+H, C₁₈H₁₆N₂O₃S).

Reference Example 10 Synthesis of ethyl3-amino-4-(3-pyridyl)-5-cyclopropylpyrrole-2-carboxylate

A 200 mL branched flask was charged with 7.764 g of(cyclopropyl-p-toluenesulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile(22.8 mmol), and 70 mL of ethanol and 35 mL of tetrahydrofuran wereadded thereto, followed by adding 5.08 g of diethylaminomalonatehydrochloric acid (24 mmol) with stirring the reaction mixture at 0° C.,and stirring at 0° C. for 1 hour. Subsequently, 35 mL of an ethanolsolution of sodium ethoxide (5.43 g, 80 mmol) was added dropwise to thereaction solution and stirred at 0° C. for 1 hour. After the completionof the reaction, the solvent was concentrated under reduced pressure andconcentrated. To the residue were added 150 mL of water and ethyl 100 mLof acetate for extraction. The aqueous layer was extracted with 50 mL ofethyl acetate. The organic layer was washed once with 100 mL of waterand three times with 50 mL of saturated brine solution. The organiclayer was dehydrated and dried over magnesium sulfate, filtered andconcentrated to obtain 3.90 g of a crude product, which was thenpurified by column chromatography (silica gel 100 g; using 4:1 to 0:1hexane/ethyl acetate as an eluent) to obtain the title compound (1.074g, yield 17%). The NMR data and ESI/MS data of the compound are givenbelow.

¹H-NMR (270 MHz, CDCl₃) δ(ppm): 0.60-0.95 (m, 4H) 1.30 (m, 1H), 1.36 (t,J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.35 (brds, 2H), 7.15 (m, 1H),7.75 (m, 1H), 8.50 (m, 1H), 8.75 (s, 1H). ESI/MS m/e: 272.1 (M⁺+H,C₁₅H₁₇N₃O₂).

Reference Example 11 Synthesis ofN-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A 3.0 mL phosphorus oxychloride solution ofN-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide(333 mg) was stirred at 110° C. for 2 hours. The reaction mixture wascooled to room temperature, and excess phosphorus oxychloride wasdistilled off under reduced pressure. The residue was dried in vacuo toobtain a crude product of the title compound, which was used for thesubsequent reaction without further purification. The ESI/MS data of thecompound are given below.

ESI/MS m/e: 535.2 (M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 12 Synthesis ofN-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared fromN-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamidein a similar manner to that described in Reference Example 11. TheESI/MS data of the compound are given below.

ESI/MS m/e: 489.0 (M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 13 Synthesis ofN-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared fromN-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamidein a similar manner to that described in Reference Example 11. TheESI/MS data of the compound are given below.

ESI/MS m/e: 443.4 (M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

Reference Example 14 Synthesis ofN-(2-{7-[(1E)-1-aza-2-(dimethylamino)vinyl]-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl}ethyl)(4-fluorophenyl)carboxyamide

N-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl)carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide(1.09 g) was used to obtain a crude product (0.87 g) of the titlecompound in the same way as Reference Example 11. NMR data and ESI/MSdata of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.81 (brs, 1H), 2.97 (brs, 1H), 3.28(s, 2H), 3.37-3.45 (m, 2H), 7.17-7.27 (m, 3H), 7.55-7.68 (m, 2H), 7.86(d, J=5.4, 1H), 8.31-8.38 (m, 1H), 8.61 (s, 1H), 8.75 (s, 1H). ESI/MSm/e: 505.4 (M⁺+H, C₂₂H₁₉Cl₂FN₆OS)

Example 1 Synthesis of5-{2-[(t-butoxy)carbonylamino]ethyl}-6-{3-chloro(2-thienyl)}-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide(Compound No: 950)

(t-butoxy)-N-{2-[6-{3-chloro(2-thienyl)}-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(3.0 g) was dissolved in ethanol (100 mL), and a 5M aqueous sodiumhydroxide solution (20 mL) was added thereto. A 30% hydrogen peroxidesolution (30 mL) was added to the reaction mixture over 20 minutes withstirring. After stirring at 45 to 50° C. for 24 hours, 30% hydrogenperoxide solution (20 mL) was added to the reaction solution, stirred at45 to 50° C. for 24 hours, concentrated and neutralized with 1 Mhydrochloric acid, to obtain a white precipitate. The precipitate wasfiltered, washed, and dried under reduced pressure to obtain the titlecompound (2.68 g, yield 86%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

HPLC retention time=7.2 (min) ¹H-NMR (270 MHz, DMSO-d₆)δ(ppm): 1.26 (s,9H), 3.2-3.5 (m, 2H), 3.8-4.0 (m, 1H), 4.4-4.6 (m, 2H), 6.5-6.6 (m, 1H),7.17 (d, 1H, J=4.6 Hz), 7.2-7.3 (m, 1H), 7.91 (d, 1H, J=5.4 Hz), 8.0-8.1(m, 1H), 12.4-12.5 (m, 1H). ESI/MS m/e: 438.3 (M⁺+H, C₁₈H₂₀ClN₅O₄S

Example 2 Synthesis of5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide(Compound No: 898)

The title compound was prepared from(t-butoxy)-N-{2-[6-cyclopropyl-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamidein a similar manner to that described in Example 1. The ESI/MS data ofthe compound are given below.

ESI/MS:m/e 362.1 (M⁺+H, C₁₇H₂₃N₅O₄)

Example 3 Synthesis ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (Compound No: 959)

5-{2-[(t-butoxy)carbonylamino]ethyl}-6-(3-chloro(2-thienyl))₄-oxo-3-hydropyrrolo[3,2-d]pyrimidine-7-carboxyamide(110 mg) was suspended in a 1 M aqueous sodium hydroxide solution (7.5mL), and benzyltrimethylammonium tribromide (135 mg) was added theretoand the mixture was stirred for 1.5 hours. 1 M hydrochloric acid wasadded to the reaction mixture to acidify the reaction system, and thenwashed with ethyl acetate. The aqueous layer was made alkaline withsodium hydrogen carbonate and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by column chromatographyon silica gel (15 g) using 1:1 to 0:1 hexane:ethyl acetate as an eluentto obtain the title compound (72 mg, yield 70%). The NMR data and ESI/MSdata of the compound are given below.

HPLC retention time=6.4 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.32 (s,9H), 3.3-3.5 (m, 2H), 4.3-4.5 (m, 2H), 4.9-5.0 (m, 1H), 7.11 (d, 1H,J=5.4 Hz), 7.54 (d, 1H, J=5.4 Hz), 7.79 (brs, 1H), 10.0-10.1 (m, 1H).ESI/MS m/e: 410.3 (M⁺+H, C₁₇H₂₀ClN₅O₃S)

Example 4 Synthesis ofN-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide(Compound No: 903)

The title compound was prepared from5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamidein a similar manner to that described in Example 3. The NMR data andESI/MS data of the compound are given below.

¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.34 (s, 9H), 0.8-1.2 (m, 5H), 3.4 (brs,2H), 3.5-3.6 (m, 3H), 4.5-4.6 (m, 2H), 5.6 (brs, 1H), 7.8 (brs, 1H)ESI/MS m/e: 334.1 (M⁺+H, C₁₆H₂₃N₅O₃)

Example 5 Synthesis of(t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No: 945)

To 30 mg ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide,1 ml of bromoform was added, followed by adding 50 μl of isoamylnitrite. After stirring at 70° C. for 4 hours, saturated brine was addedto the reaction solution, which was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated, followed by subjecting to thin layer chromatography onsilica gel using ethyl acetate as a developing solvent to obtain thetitle compound (15 mg, yield 43%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

HPLC retention time=9.5 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.31 (s,9H), 3.3-3.5 (m, 2H) 4.2-4.3 (m, 1H), 4.5-4.7 (m, 1H), 4.7-4.9 (m, 1H),7.13 (d, 1H, J=5.7 Hz), 7.60 (d, 1H, J=5.4 Hz), 7.94 (d, 1H, J=3.0 Hz).ESI/MS m/e 475.2 (M⁺+H, C₁₇H₁₈BrClN₄O₃S)

Example 6 Synthesis of(t-butoxy)-N-{2-[7-bromo-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No: 2511)

The title compound was prepared fromN-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamidein a similar manner to that described in Example 5. The HPLC retentiontime, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.5 (min) 1H-NMR (270 MHz, CDCl₃)δ(ppm): 1.31 (s,9H), 1.1-1.3 (m, 5H), 3.5-3.9 (m, 3H), 4.5-4.9 (m, 2H), 5.1-5.3 (brs,1H), 7.9 (s, 1H) ESI/MS m/e: 397.1 (M⁺+H, C₁₆H₂₁BrN₄O₂S)

Example 7 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No: 946)

To 1 g ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide,7 mL of diiodomethane was added, followed by adding 822 μl of isoamylnitrite. After stirring at 70° C. for 4 hours, saturated brine was addedto the reaction solution, which was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated, followed by subjecting to chromatography on silica gel(using 5:1 to 0:1 hexane/ethyl acetate as an eluent), to yield the titlecompound (694 g, yield: 55%). NMR data and ESI/MS data of the compoundare given below.

HPLC retention time=9.6 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.32 (s,9H), 3.3-3.5 (m, 2H), 4.2-4.35 (m, 1H), 4.6-4.75 (m, 1H), 4.8-5.0 (m,1H), 7.14 (d, 1H, J=5.4 Hz), 7.59 (d, 1H, J=5.7 Hz), 7.95-8.05 (m, 1H).ESI/MS m/e 521.3 (M⁺+H, C₁₇H₁₈ClIN₄O₃S

Example 8 Synthesis of(t-butoxy-N-{2-[7-iodo-6-cyclopropyl]-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}Ethyl)carboxyamide(Compound No: 896)

The title compound was prepared fromN-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamidein a similar manner to that described in Example 7. The HPLC retentiontime, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.7 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.31 (s,9H), 1.0-1.3 (m, 5H), 3.5-3.8 (m, 3H), 4.7-4.9 (m, 2H), 5.2-5.3 (brs,1H), 7.9 (s, 1H) ESI/MS m/e: 445.4 (M⁺+H, C₁₆H₂₁IN₄O₃)

Example 9 Synthesis of(t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No: 944)

To 20 mg ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide,2 ml of carbon tetrachloride was added, followed by adding 34 μl ofisoamyl nitrite. After refluxing for 40 hours, saturated brine was addedto the reaction solution, which was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated, followed by subjecting to thin layer chromatography onsilica gel (using ethyl acetate as a developing solvent) to obtain thetitle compound (5 mg, yield: 24%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

HPLC retention time=9.4 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.32 (s,9H), 3.3-3.5 (m, 2H), 4.15-4.4 (m, 1H), 4.6-4.75 (m, 1H), 4.8-4.95 (m,1H), 7.13 (d, 1H, J=5.4 Hz), 7.60 (d, 1H, J=5.4 Hz), 7.98 (brs, 1H).ESI/MS m/e 429.4 (M⁺+H, C₁₇H₁₈Cl₂N₄O₃S)

Example 10 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 943)

To 15 mg ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide,2 mL of tetrahydrofuran was added, followed by adding 50 μl of isoamylnitrite. After stirring at 50° C. for 3 hours, saturated brine was addedto the reaction solution, which was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated, followed by subjecting to thin layer chromatography onsilica gel (developing solvent: ethyl acetate) to obtain the titlecompound (8 mg, yield 55%). The NMR data and ESI/MS data of the compoundare given below.

HPLC retention time=8.4 (min) ¹H-NMR (270 MHz, CDCl₃) δ(ppm): 1.31 (s,9H), 3.3-3.5 (m, 2H) 4.4-4.6 (m, 2H), 5.01 (brs, 1H), 6.66 (s, 1H), 7.07(d, 1H, J=5.4 Hz), 7.49 (d, 1H, J=5.1 Hz), 7.93 (brs, 1H), 11.2-11.3 (m,1H). ESI/MS m/e 395.2 (M⁺+H, C₁₇H₁₉ClN₄O₃S)

Example 11 Synthesis of5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (Compound No. 206)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(331 mg) was dissolved in a mixed solution of methanol (0.5 mL) and1,4-dioxane (5.0 mL), and hydrochloric acid/1,4-dioxane solution (4mol/L, 0.64 mL) was added and the mixture was stirred at 60° C. for 2hours. The reaction mixture was cooled to room temperature, and thesolvent was distilled off under reduced pressure. The residue was driedunder reduced pressure to obtain the title compound (334 mg in aquantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 421.2 (M⁺+H, C₁₂H₁₀ClN₄OS HCl)

Example 12 Synthesis of5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (Compound No. 205)

The title compound was prepared from(t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamidein a similar manner to that described in Example 11. The ESI/MS data ofthe compound are given below.

ESI/MS m/e: 375.0 (M⁺+H, C₁₂H₁₀BrClN₄OS HCl)

Example 13 Synthesis of5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (Compound No. 204)

The title compound was prepared from(t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamidein a similar manner to that described in Example 11. The ESI/MS data ofthe compound are given below.

ESI/MS m/e: 329.4 (M⁺+H, C₁₂H₁₀Cl₂N₄OS HCl)

Example 14 Synthesis ofN-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide(Compound No. 320)

To a tetrahydrofuran (5.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (259 mg) was added trifluoroacetic anhydride (595 mg), andtriethylamine (1.2 mL) was added slowly dropwise. The reaction mixturewas stirred at room temperature for 2 hours, and methanol was added tostop the reaction. The solvent was distilled off under reduced pressure.To the residue were added water and ethyl acetate, which was extracted 3times with ethyl acetate. The organic layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. After anhydrousmagnesium sulfate was filtered off, the solvent was distilled off underreduced pressure. The residue was dried under reduced to obtain a crudeproduct (365 mg) of the title compound. The HPLC retention time, NMRdata and ESI/MS data of the compound are given below.

HPLC retention time=9.1 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 3.45 (m,2H), 4.16 (m, 1H) 4.61 (m, 1H), 7.30 (m, 1H), 7.93 (m, 1H), 8.02 (m,1H), 9.37 (m, 1H), 12.29 (brs, 1H). ESI/MS m/e: 517.2 (M⁺+H,C₁₄H₉ClF₃₁N₄O₂S)

Example 15 Synthesis ofN-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide(Compound No. 319)

The title compound was prepared from5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride in a similar manner to that described in Example 14. TheESI/MS data of the compound are given below.

ESI/MS m/e: 471.1 (M⁺+H, C₁₄H₉BrClF₃N₄O₂S)

Example 16 Synthesis ofN-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide(Compound No. 318)

The title compound was prepared from5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride in a similar manner to that described in Example 14. TheESI/MS data of the compound are given below.

ESI/MS m/e: 425.4 (M⁺+H, C₁₄H₉Cl₂F₃N₄O₂S)

Example 17 Synthesis ofN-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide(Compound No. 344)

To an N,N-dimethylacetamide (2.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (33 mg) was added 4-fluorobenzoylchloride (23 mg), and themixture was stirred at room temperature for a short time, followed byadding triethylamine (0.2 mL) and stirring at room temperature for 2hours. To the reaction solution was added water (0.2 mL), and thesolution was stirred again at room temperature overnight. The solventwas distilled off under reduced pressure, and the residue was purifiedby fraction HPLC to obtain the title compound (22 mg, yield 55%). TheHPLC retention time, NMR data and ESI/MS data of the compound are givenbelow.

HPLC retention time=9.1 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 3.52 (m,2H), 4.24 (m, 1H), 4.63 (m, 1H), 7.19-7.26 (m, 3H), 7.70-7.74 (m, 2H),7.88-7.92 (m, 2H), 8.45 (m, 1H), 12.24 (brs, 1H). ESI/MS m/e: 543.4(M⁺+H, C₁₉H₁₃ClFIN₄O₂S)

Example 18 Synthesis of6-(3-chloro(2-thienyl))-7-iodo-5-[2-(quinazolin-4-ylamino)ethyl]-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 81)

To an N,N-dimethylacetamide (2.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (36 mg) and 4-chloroquinazoline (10 mg), was addedtriethylamine (16 mg) and the mixture was stirred at 70° C. for 2 hours.Triethylamine (32 mg) was further added to the reaction mixture andstirred at 70° C. for 2 hours. The reaction mixture was cooled to roomtemperature and purified by fraction HPLC to obtain the title compound(21 mg, yield 49%). The HPLC retention time, NMR data and ESI/MS data ofthe compound are given below.

HPLC retention time: 6.9 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 3.95 (m,2H), 4.48 (m, 1H) 4.87 (m, 1H), 7.12 (m, 1H), 7.71-7.82 (m, 3H), 7.87(brs, 1H), 8.00 (t, J=7.7, 1H), 8.18 (d, J=8.3, 1H), 8.60 (s, 1H), 9.91(brs, 1H), 12.24 (brs, 1H). ESI/MS m/e: 549.4 (M⁺+H, C₂₀H₁₄ClIN₆OS)

Example 19 Synthesis ofN-(5-{2-[(t-butoxy)carbonylamino]ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide(Compound No. 962)

To a tetrahydrofuran solution (39 mL) ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide(1.60 g) was added triethylamine (2.7 mL), and cooled to 0° C., followedby adding trifluoroacetic anhydride (1.35 mL) slowly dropwise. Thereaction mixture was stirred at room temperature for 1 hour, andsaturated brine was added dropwise to stop the reaction. Ethyl acetatewas added to the reaction solution for extraction. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andfiltered. The solvent was distilled off under reduced pressure to obtainthe title compound (1.97 g, a quantitative yield) as a light yellowsolid. The HPLC retention time, NMR data and ESI/MS data of the compoundare given below.

HPLC retention time=8.7 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.26 (s,9H), 3.13-3.26 (m, 2H), 4.11 (brs, 1H), 4.49 (brs, 1H), 6.60-6.73 (m,1H), 7.23 (d, J=5.4, 1H), 7.88 (s, 1H), 7.95 (d, J=5.4, 1H), 10.86 (s,1H), 12.21 (brs, 1H). ESI/MS m/e: 506.4 (M⁺+H, C₁₉H₁₉ClF₃N₅O₄S)

Example 20 Synthesis ofN-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoroacetamidehydrochloride (Compound No. 207)

A methanol solution (13 mL) ofN-(5-{2-[(t-butoxy)carbonylamino]ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide(1.97 g) was cooled to 0° C. and added was 4 mol/L hydrochloricacid/1,4-dioxane solution (26 mL), followed by stirring at roomtemperature for 4 hours. The solvent was distilled off under reducedpressure, yielding a crude product (1.73 g) of the title compound. TheESI/MS data of the compound are given below.

ESI/MS m/e: 406.3 (M⁺+H, C₁₄H₁₁F₃N₅O₂S.HCl)

Example 21 Synthesis ofN-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl)carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide(Compound No. 345)

N-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoro-acetamidecrude product (1.73 g) in pyridine (39 mL) was cooled to 0° C., and4-fluorobenzoylchloride (0.92 mL) was added thereto, followed bystirring at room temperature for 1 hour. To the reaction solution wasadded water (40 mL), stirred at room temperature for 1 hour, and to stopthe reaction. Brine was added until the reaction solution was saturated,and extraction with ethyl acetate was performed. The organic layer waswashed with a mixed solution of saturated brine and 1 mol/L ofhydrochloric acid (9:1), dried over anhydrous sodium sulfate andfiltered. The solvent was distilled off under reduced pressure andpurified by column chromatography on silica gel using 1/2 hexane/ethylacetate and then using ethyl acetate only as eluents to obtain the titlecompound (1.60 g, 78% yield for 2 steps). The HPLC retention time, NMRdata and ESI/MS data of the compound are given below.

HPLC retention time=8.3 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(PPM): 3.49-3.58(m, 2H) 4.34 (brs, 1H), 4.66 (brs, 1H), 7.16 (d, J=5.4, 1H), 7.19 (t,J=7.1, 2H), 7.65-7.75 (m, 2H), 7.83 (d, J=5.4, 1H), 7.88 (s, 1H),8.40-8.50 (m, 1H), 10.85 (s, 1H), 12.25 (brs, 1H). ESI/MS m/e: 528.4(M⁺+H, C₂₁H₁₄ClF₄N₅O₃S)

Example 22 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 965)

To a tetrahydrofuran solution (10 mL) ofN-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide(0.41 g) was added triethylamine (0.69 mL), and the reaction mixture wascooled to 0° C. and benzoylchloride (0.29 mL) was added slowly dropwise.The reaction mixture was stirred at room temperature for 1 hour, and anaqueous sodium hydroxide solution (2 mol/L, 2.0 mL) was added dropwiseand stirred for 18 hours to stop the reaction. Hydrochloric acid (1mol/L, 4.0 mL) was added to the reaction solution for neutralization,brine was added thereto until the reaction solution was saturated, andextraction with ethyl acetate was performed. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate andfiltered. The solvent was distilled off under reduced pressure, andpurified by column chromatography was performed on silica gel usingethyl acetate only to obtain the title compound (0.51 g, a quantitativeyield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 514.4 (M⁺+H, C₂₄H₂₄ClN₅O₄S)

Example 23 Synthesis ofN-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamidehydrochloride (Compound No. 208)

To a methanol solution (3.3 mL) of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(0.51 g) was added 4 mol/L hydrochloric acid/1,4-dioxane solution (6.6mL) and the mixture was stirred at room temperature for 5 hours. Thesolvent was distilled off under reduced pressure, yielding a crudeproduct (0.47 g) of the title compound. The ESI/MS data of the compoundare given below.

ESI/MS m/e: 414.3 (M⁺+H, C₁₉H₁₆ClN₅O₂.HCl)

Example 24 Synthesis ofN-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide(Compound No. 346)

To a dimethylacetamide solution (1.0 mL) ofN-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide(45 mg), were added 4-fluorobenzoylchloride (23.6 μL) and triethylamine(55 μL) and the mixture was stirred at room temperature for 1 hour. 2mol/L of an aqueous sodium hydroxide solution (1.0 mL) was addeddropwise, and the solution was stirred for 1 hour and stopped thereaction. 1 mol/L of hydrochloric acid (2.0 mL) was added to thereaction solution for neutralization, brine was added thereto until thereaction solution was saturated, and extraction with ethyl acetate wasperformed. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate and filtered. The solvent was distilled offunder reduced pressure, and purified by fraction HPLC to obtain thetitle compound (25.5 mg, yield 48%). The HPLC retention time, NMR dataand ESI/MS data of the compound are given below.

HPLC retention time=8.2 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):3.50-3.70 (m, 2H), 4.35 (brs, 1H), 4.68 (brs, 1H), 7.12 (d, J=5.4, 1H),7.22 (t, J=8.8, 2H), 7.44 (t, J=7.3, 2H), 7.47-7.56 (m, 1H), 7.69-7.78(m, 3H), 7.84 (d, J=7.6, 2H), 7.89 (s, 1H), 8.47 (t, J=5.4, 1H), 9.72(s, 1H), 12.22 (brs, 1H). ESI/MS m/e: 536.4 (M⁺+H, C₂₆H₁₉ClFN₅O₃S)

Example 25 Synthesis ofN-{6-(3-chloro(2-thienyl))-4-oxo-5-[2-(quinazolin-4-ylamino)ethyl](3-hydropyrrolo[3,2-d]pyrimidin-7-yl)}benzamide(Compound No. 82)

N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide(45 mg) and 4-chloroquinazoline (16.5 mg) were dissolved indimethylacetamide (2.9 mL), and triethylamine (27.7 μL) was addedthereto and the mixture was stirred at 70° C. for 3 hours. Triethylamine(13.9 μL) was further added to the reaction mixture and the solution wasstirred at 70° C. for 5 hours. The reaction solution was cooled to roomtemperature and purified by fraction HPLC, to obtain the title compound(44.3 mg, 82%). The HPLC retention time, NMR data and ESI/MS data of thecompound are given below.

HPLC retention time=6.4 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 3.95-4.05(m , 2H), 4.52 (brs, 1H), 5.00 (brs, 1H), 7.05 (d, J=5.4, 1H), 7.43 (t,J=7.6, 2H), 7.52 (t, J=7.3, 1H), 7.65 (d, J=5.4, 1H), 7.70-7.85 (m, 5H),8.02 (t, J=7.8, 1H), 8.23 (d, J=8.5, 1H), 8.61 (s, 1H), 9.66 (s, 1H),10.17 (m, 1H), 12.10 (brs, 1H). ESI/MS m/e: 542.4 (M⁺+H, C₂₇H₂₀ClN₇O₂S)

Example 26 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-vinyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 966)

A nitrogen flushed flask was charged with a 0.5 M zincchloride/tetrahydrofuran solution, and 1.0 mL of a 1.0 M vinyl magnesiumbromide/tetrahydrofuran solution was added thereto with stirring, themixture solution was stirred for 30 minutes, to obtain a suspensionwhich was used in a subsequent reaction. To a round-bottom flask, weretransferred 26 mg of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamideand 12 mg of tetrakistriphenylphosphine palladium (O), followed byflushing with nitrogen and adding 2 mL dry tetrahydrofuran thereto. 600μl of the suspension was added to the reaction mixture and the mixturewas stirred at 50° C. for 8 hours, and saturated brine was added theretoand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The obtained crudeproduct was subjected to chromatography on silica gel (eluent: 5:1 to0:1 hexane:ethyl acetate), to obtain the title compound (5.5 mg, yield26%). The HPLC retention time and ESI/MS data of the compound are givenbelow.

HPLC retention time=9.6 (min) EMS/MS m/e 421.2 (M⁺+H, C₁₉H₂₁ClN₄O₃S)

Example 27 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-(3-hydroxy-1-prop-1-ynyl)-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 971)

A round-bottom flask was charged with 26 mg of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide,12 mg of tetrakistriphenylphosphine palladium, 3.8 mg of copper (I)iodide and 15 μl of propargyl alcohol, followed by flushing withnitrogen, and 1 mL of dry tetrahydrofuran and 209 μl of triethylaminewere added thereto. The reaction mixture was stirred at 50° C. for 5hours, and saturated brine was added thereto and extracted with ethylacetate. The organic layer was concentrated and subjected to columnchromatography on silica gel, (developing solvent: 10 mL of toluene to 8mL of ethyl acetate:methanol=2:1). A portion eluted by ethylacetate/methanol was concentrated and subjected to fraction HPLC toobtain the title compound. The HPLC retention time and ESI/MS data ofthe compound are given below.

HPLC retention time=9.0 (min) EMS/MS m/e 448.9 (M+H⁺, C₂₀H₂₁ClN₄O₄S)

Example 28 Synthesis ofN-{2-[7-benzo[d]furan-2-yl-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide(Compound No. 1000)

A round-bottom flask was charged with 26 mg of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide,2.2 mg of palladium acetate, triphenylphosphine, 26 mg of sodiumcarbonate and 16.2 mg of 2-benzofuranyl boric acid and flushed withnitrogen. 1 mL of a solution containing dimethylformamide and watermixed in a ratio of 2:1 was added to the reaction mixture and themixture was stirred at 80° C. for 24 hours, and saturated brine wasadded thereto and extracted with ethyl acetate. The organic layer wasconcentrated and subjected to chromatography on silica gel, (developingsolvent: 10 mL of toluene to 8 mL of ethyl acetate/methanol=2:1). Aportion eluted by ethyl acetate/methanol was concentrated and subjectedto fraction HPLC to obtain the title compound. The HPLC retention timeand ESI/MS data of the compound are given below.

HPLC retention time=11.6 (min) EMS/MS m/e 511.3 (M+H⁺, C₂₅H₂₃ClN₄O₄S)

Example 29 Synthesis ofN-{2-[6-(3-chloro-thiophen-2-yl)-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide(Compound No. 625)<

To an N,N-dimethylacetamide solution (5.0 mL) of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-onehydrochloride (173 mg) was added t-butylacetyl chloride (95 mg) and themixture was stirred at room temperature for a short time, followed byadding triethylamine (1.0 mL) and stirring at room temperature for 2hours. To the reaction solution was added water (1.0 mL) and further thesolution was stirred at room temperature overnight. The obtainedsolution was extracted with ethyl acetate (10 mL×2). The organic layerwas washed with saturated brine, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by columnchromatography on silica gel (using ethyl acetate only) to obtain thetitle compound (160 mg, yield: 88%). The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 0.84 (s, 9H), 1.81 (d, J=3.67, 2H),3.25-3.34 (m, 2H), 4.05-4.12 (m, 1H), 4.44-4.50 (m, 1H), 7.28 (d,J=5.36, 1H), 7.69 (t, J=5.86, 1H), 7.92 (d, J=3.67, 1H), 8.00 (d,J=5.36, 1H), 12.25 (brs, 1H). ESI/MS m/e: 519.1 (M⁺+H, C₁₈H₂₀ClIN₄O₂S)

Example 30 Synthesis ofN-{2-[7-(1H-pyrazol-4-yl)-6-(3-chloro-thiophen-2-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide(Compound No. 629)

To a screw-cap vial were transferredN-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide(26 mg), palladium acetate (2.2 mg), triphenylphosphine (5.2 mg), sodiumcarbonate (26 mg) and4-(4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1H-pyrazole (19.4mg), and flushed with nitrogen. A 2:1 dimethylformamide:water solution(1 mL) was added to the reaction mixture and the mixture was stirred at80° C. for 12 hours. Saturated brine was added to the obtained solutionand extracted with ethyl acetate. The organic layer was concentrated andpurified by fraction HPLC to obtain the title compound (5.2 mg, yield23%). The HPLC retention time, NMR data and ESI/MS data of the compoundare given below.

HPLC retention time=10.9 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 0.85(s, 9H), 1.84 (d, J=1.68, 2H), 3.30-3.38 (m, 2H), 4.04-4.11 (m, 1H),4.35-4.40 (m, 1H), 7.34 (d, J=5.38, 1H), 7.44 (brs, 2H), 7.76 (t,J=5.60, 1H), 7.93 (s, 1H), 8.05 (d, J=5.38, 1H), 12.17 (brs, 1H). EMS/MSm/e 459.3 (M+H⁺, C₂₁H₂₃ClN₆O₂S

Example 31 Synthesis of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 209) dihydrochloride

(t-butoxy)-N-{2-[6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}carboxyamide(1.68 g) was dissolved in methanol (10.0 mL), followed by adding 4 mol/Lhydrochloric acid/1,4-dioxane solution (2.0 mL) thereto and stirring at60° C. for 12 hours. The reaction mixture was cooled to roomtemperature, and the solvent was distilled off under reduced pressure.The residue was dried under reduced pressure to obtain the titlecompound (1.64 g, a quantitative yield). The ESI/MS data of the compoundare given below.

ESI/MS m/e: 371.9 (M⁺+H, C₁₇H₁₄ClN₅OS 2HCl)

Example 32 Synthesis of1-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-phenylurea(Compound No. 793)

To an N,N-dimethylformamide (1.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-onedihydrochloride (25 mg) was added phenylisocyanate (20 mg) and themixture was stirred at room temperature for a short time, followed byadding triethylamine (0.2 mL) and stirring at room temperature for 2hours. Saturated brine was added to the obtained solution and extractedwith ethyl acetate. The reaction solution was distilled off underreduced pressure, and the residue was purified by fraction HPLC toobtain the title compound (8 mg, yield 29%). The HPLC retention time andESI/MS data of the compound are given below.

HPLC retention time=6.6 (min) ESI/MS m/e: 491.04 (M⁺+H, C₂₄H₁₉ClN₆O₂S

Example 33 Synthesis of4-fluoropiperidine-1-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide(Compound No. 550)

To a chloroform (1.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-onedihydrochloride (25 mg) were added triethylamine (0.078 mL) andtriphosgene (17 mg) and the mixture was stirred at room temperature fora short time, and 4-fluoropiperidine (12 mg) was added thereto followedby stirring at room temperature for 3 hours. Saturated brine was addedto the obtained solution and extracted with ethyl acetate. The reactionsolution was distilled off under reduced pressure, and the residue waspurified by fraction HPLC to obtain the title compound (1.2 mg, yield5%). The HPLC retention time and ESI/MS data of the compound are givenbelow.

HPLC retention time=6.9 (min) ESI/MS m/e: 501.41 (M⁺+H, C₂₃H₂₂ClFN₆O₂S)

Example 34 Synthesis of5-[2-(bis(cyclopropylmethyl)amino)ethyl]-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 1057)

To an N,N-dimethylformamide (1.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-onedihydrochloride (25 mg) were added cyclopropyl aldehyde (5 mg), sodiumtriacetoxy borohydride (24 mg) and acetic acid (0.1 mL) and the mixturewas stirred at room temperature for 10 hours. Saturated brine was addedto the obtained solution and extracted with ethyl acetate. The reactionsolution was distilled off under reduced pressure, and the residue waspurified by fraction HPLC to obtain the title compound (10 mg, yield36%). The HPLC retention time and ESI/MS data of the compound are givenbelow.

HPLC retention time=5.4 (min) ESI/MS m/e: 482.0 (M⁺+H, C₂₅H₂₆ClFN₅OS)

Example 35 Synthesis ofN-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide(Compound No. 626)

To an N,N-dimethylacetamide (1.0 mL) solution of5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-onedihydrochloride (25 mg) was added t-butylacetyl chloride (23 mg) and themixture was stirred at room temperature for a short time, followed byadding triethylamine (0.2 mL) and stirring at room temperature for 2hours. Water (0.2 mL) was added to the reaction solution and thesolution was stirred again at room temperature overnight. Saturatedbrine was added to the obtained solution and extracted with ethylacetate. The reaction solution was distilled off under reduced pressure,and the residue was purified by fraction HPLC to obtain the titlecompound (19 mg, yield 72%). The HPLC retention time and ESI/MS data ofthe compound are given below.

HPLC retention time=7.6 (min) ESI/MS m/e: 470.1 (M⁺+H, C₂₃H₂₄ClN₅O₂S)

Example 36 Synthesis of1-methyl-cyclohexane-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide(Compound No. 684)

To an N,N-dimethylformamide (1.0 mL) solution of5-(2-aminoethyl)-6-(3-chlorothiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-onedihydrochloride (25 mg) were added 1-methyl-cyclohexanecarboxylic acid(24 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carboxyamide hydrochloride(43 mg), N-hydroxybenzotriazole (8 mg) and triethylamine (0.2 mL) andthe mixture was stirred at room temperature for 10 hours. Saturatedbrine was added to the obtained solution and extracted with ethylacetate. The reaction solution was distilled off under reduced pressure,and the residue was purified by fraction HPLC to obtain the titlecompound (11 mg, yield 41%). The HPLC retention time and ESI/MS data ofthe compound are given below.

HPLC retention time=8.2 (min) ESI/MS m/e: 496.0 (M⁺+H, C₂₅H₂₆ClN₅O₂S)

Example 37 Synthesis ofN-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide(Compound No. 217)

To a 1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(356 mg) was added 4 mol/L hydrochloric acid/dioxane solution (0.75 mL)and the mixture was stirred 60° C. for 1 hour. The reaction solution wascooled to room temperature, and the solvent was distilled off underreduced pressure. The residue was dried under reduced pressure to obtaincrude product (370 mg). To a dimethylacetamide solution (2.0 mL) of thereaction product (26 mg) were added chloroacetyl (10 mg) andtriethylamine (0.2 mL) and the mixture was stirred at room temperaturefor 1 hour, followed by adding water (0.2 mL) and further stirring atroom temperature for 1 hour. Purification by fraction HPLC was performedto obtain the title compound (15 mg, yield 57%). The HPLC retentiontime, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.7 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.65 (s,3H), 3.31-3.41 (m, 2H), 4.16 (m, 1H), 4.50 (m, 1H), 7.29 (m, 1H), 7.61(dd, J=5.12, J=8.08, 1H), 7.86 (m, 1H), 7.92 (m, 1H), 8.01 (m, 2H), 8.54(d, J=5.12, 1H), 8.64 (s, 1H), 12.38 (brs, 1H). ESI/MS m/e: 414.4 (M⁺+H,C₁₉H¹⁶ClN₅O₂S)

Example 38 Synthesis of6-(3-chloro(2-thienyl))-7-(3-pyridyl)-5-[2-quinazolin-4-ylamino]ethyl]-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 84)

A 4 mol/L hydrochloric acid/dioxane solution (0.75 mL) was added to a1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(356 mg) and the mixture was stirred at 60° C. for 1 hour. The reactionsolution was cooled to room temperature, and the solvent was distilledoff under reduced pressure. The residue was dried under reduced pressureto obtain a crude product (370 mg). To a dimethylacetamide (2.0 mL)solution of the reaction product (32 mg) were added 4-chloroquinazoline(13 mg) and triethylamine (16 mg) and the solution was stirred at 70° C.for 2 hours. The reaction solution was cooled to room temperature, andpurification by fraction HPLC was performed to obtain the title compound(21 mg, yield 54%). The HPLC retention time, NMR data and ESI/MS data ofthe compound are given below.

HPLC retention time=5.6 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):4.01-4.06 (m, 2H), 4.55 (m, 1H), 4.96 (m, 1H), 7.08 (m, 1H), 7.47 (dd,J=4.88, J=8.04, 1H), 7.72-7.78 (m, 3H), 7.83 (m, 1H), 7.90 (s, 1H), 8.02(t, J=7.68, 1H), 8.23 (d, J=8.52, 1H), 8.46 (d, J=5.12, 1H), 8.52 (s,1H), 8.67 (s, 1H), 10.18 (m, 1H), 12.30 (brs, 1H). ESI/MS m/e: 500.4(M⁺+H, C₂₅H₁₈ClN₇OS)

Example 39 Synthesis of ethyl3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate(Compound No. 35)

To an isopropyl alcohol (80 mL) solution of ethyl3-[3-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl]propanate (4.380 g)was added formamidine acetate (7.184 g) and the mixture was stirred at90° C. for 10 hours. The reaction solution was cooled to roomtemperature, and the solid was subjected to fractional filtration. Theextractant was distilled off under reduced pressure. To the residue wasadded water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried with sodium sulfate, which wasthen subjected to fractional filtration. Then, the solvent was distilledoff under reduced pressure. The residue was purified by columnchromatography on silica gel (ethyl acetate:ethanol=7:1), to obtain thetitle compound (0.747 g, yield 17%). The HPLC retention time, NMR dataand ESI/MS data of the compound are given below.

HPLC retention time=5.6 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.11 (t,J=7.08, 3H), 2.95 (t, J=6.96, 2H), 4.03 (dd, J=6.96, J=14.28, 2H), 4.63(t, J=6.84, 2H), 7.81 (dd, J=5.12, J=8.04, 1H), 7.99 (s, 1H), 8.22 (s,1H), 8.60 (d, J=5.12, 1H), 8.81 (d, J=8.04, 1H), 9.38 (s, 1H), 12.29 (s,1H). ESI/MS m/e: 313.2 (M⁺+H, C₁₆H₁₆N₄O₃)

Example 40 Synthesis of3-(4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-phenylpropaneamide(Compound No. 30)

Water (0.40 mL) and a 5 M aqueous sodium hydroxide solution (0.18 mL)were added to a 1,4-dioxane (3.0 mL) solution of ethyl3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate (91mg) and the mixture was stirred at room temperature for 2 hours. Thereaction solution was neutralized with acetic acid, and the resultingsolid was filtered and washed with water and ethyl acetate to obtain acrude product (78 mg). 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (41 mg) and pyridine (0.2 mL) were added to a mixedsolution of dichloromethane (1.0 mL) and dimethylacetamide (1.0 mL) ofthe reaction product (20 mg) and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added aniline (20mg) and the solution was stirred at 40° C. overnight. Methanol was addedto stop the reaction, and the solvent was distilled off under reducedpressure. The residue was purified by fraction HPLC to obtain the titlecompound (19 mg, yield 76%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

HPLC retention time=6.1 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 2.97 (t,J=6.58, 2H) 4.69 (t, J=6.48, 2H), 6.99 (t, J=7.46, 1H), 7.24 (t, J=7.92,2H), 7.51 (d, J=8.56, 2H), 7.78 (dd, J=5.50, J=7.94, 1H), 7.99 (s, 1H),8.18 (s, 1H), 8.57 (d, J=5.40, 1H), 8.78 (d, J=8.04, 1H), 9.36 (s, 1H),9.96 (s, 1H), 12.30 (brs, 1H). ESI/MS m/e: 360.2 (M⁺+H, C₂₀H₁₇N₅O₂)

Example 41 Synthesis of6-chloro-5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 1180)

N-chlorosuccinimide (57 mg) was added to a dimethylformamide (2.0 mL)solution of 5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one(65 mg) and the mixture was stirred at room temperature for 2 hours.N-chlorosuccinimide (57 mg) was added to the reaction mixture andfurther the mixture was stirred at room temperature for 2 hours. Water(0.2 mL) was added to stop the reaction, and purification by fractionHPLC gave the title compound (33 mg, yield 46%). The HPLC retentiontime, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.0 (min) ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 5.82 (s,2H), 7.22-7.36 (m, 5H), 7.72 (dd, J=5.12, J=8.04, 1H), 8.00 (s, 1H),8.42 (m, 1H), 8.64 (d, J=5.12, 1H), 9.07 (s, 1H), 12.41 (brs, 1H).ESI/MS m/e: 337.3 (M⁺+H, C₁₈H₁₃ClN₄O

Example 42 Synthesis of7-(3-pyridyl)-4-oxo-6-cyclopropyl-3-hydropyrrolo[3,2-d]pyrimidine(Compound No. 1178)

To a 100 mL branched flask was transferred ethyl3-amino-4-(3-pyridyl)-5-cyclopropyl pyrrole-2-carboxylate (118 mg), andisopropylalcohol (40 mL) and formamidine acetate (1.35 g) were addedthereto and heated at 95° C. for 13 hours with stirring. After thecompletion of the reaction, the solvent was concentrated under reducedpressure. To the concentrated residue were added water (20 mL) and ethylacetate (20 mL) for separation. The aqueous layer was extracted againwith 20 mL ethyl acetate. The organic layer was washed twice with 20 mLwater, dehydrated and dried with magnesium sulfate, filtered andconcentrated to obtain a crude product (91 g). The crude product waswashed 3 times with 1 mL methanol to yield the title compound (49 mg,yield 45%). The ESI/MS data of the compound are given below.

HPLC retention time=4.2 (min) ESI/MS m/e: 253.1 (M⁺+H, C₁₄H₁₂N₄O)

Example 43 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(trifluoromethyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 947)

Under nitrogen atmosphere, a dry dimethylformamide suspension (10 mL) ofcadmium (2.24 g) was cooled on ice with stirring, anddibromodifluoromethane (1.5 mL) was added thereto, followed by stirringat room temperature for 3 hours. Dry hexamethylphosphoramide (10 mL) wasadded to the reaction solution and cooled on ice, and copper (I) bromide(1.16 g) was added to the reaction mixture and the mixture was stirredat room temperature for 1 hour to obtain a copper trifluoromethylcompound suspension.

The copper trifluoromethyl compound suspension (10 mL) was added to adry dimethylformamide solution (3 mL) of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(115 mg) and the solution was stirred at 65° C. for 6 hours. An aqueousammonium chloride solution was added to the reaction solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered, concentrated, and purified bychromatography on silica gel, to obtain the title compound (35 mg, 34%).The HPLC retention time, NMR data and ESI/MS data of the compound aregiven below.

HPLC retention time=12.1 (min) ¹H-NMR (270 MHz, CDCl₃)δ(ppm): 1.32 (s,9H), 3.35-3.60 (m, 2H), 4.00-4.30 (m, 1H), 4.40-4.70 (m, 1H), 7.11 (d,J=5.1 Hz, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.95-8.10 (m, 1H). ESI/MS m/e:463.2 (M⁺+H, C₁₈H₁₈ClF₃N₄O₃S)

Example 44 Synthesis of6-phenyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (CompoundNo. 2445)

An N,N-dimethylformamide/water (2:1) solution (1.0 mL) of6-chloro-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (40 mg),phenyl boric acid (59 mg), and potassium acetate (78 mg) was subjectedto deaeration, and a small amount of[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloridedichloro-methane (1:1) complex was added thereto. The reaction mixturewas heated at 140° C. for 5 minutes by using microwaves. The solvent wasdistilled off under reduced pressure and the residue was separated toethyl acetate and aqueous layers. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution and brine and driedover sodium sulfate. The sodium sulfate was filtered, and solvent wasdistilled off under reduced pressure. The residue was purified bychromatography on silica gel (0-5% methanol/ethyl acetate), and furtherpurified by fraction HPLC to obtain the title compound (6.3 mg, yield10%). The HPLC retention time, NMR data and ESI/MS data of the compoundare given below.

HPLC retention time: 4.0 (min) ¹H-NMR (400 MHz, CD₃OD)δ(ppm): 7.50 (m,5H), 7.86 (dd, J=5.7, J=8.2, 1H), 7.98 (s, 1H), 8.44 (dt, J=1.6, J=8.2,1H), 8.62 (d, J=5.7, 1H), 8.94 (s, 1H). ESI/MS m/e: 289.1 (M⁺+H,C₁₇H₁₂N₄O)

Example 45 Synthesis of ethyl4-(4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No.2501)

An ethyl 4-[3-amino-2-(ethoxycarbonyl)pyrolyl]butanoate hydrochloride(20.1 g) was dissolved in dichloromethane (400 mL), and saturatedaqueous sodium hydrogen carbonate (400 mL) was added thereto. Thereaction mixture was vigorously stirred for 30 minutes, and two layerswere separated. The aqueous layer was extracted with dichloromethane,and combined organic layer was washed with saturated brine, and driedover magnesium sulfate. The magnesium sulfate was filtered, and thesolvent was distilled off under reduced pressure to obtain ethyl4-[3-amino-2-(ethoxycarbonyl)pyrolyl]butanoate (18.0 g). This compoundwas dissolved in isopropylalcohol (400 mL), and formamidine acetate(9.78 g) was added thereto. This mixture was heated for 150 minutes toreflux. The solvent was distilled off under reduced pressure and theresidue was separated to dichloromethane and aqueous layers. The aqueouslayer was extracted with dichloromethane, and the combined organic layerwas washed with 10% aqueous citric acid solution, saturated aqueoussodium hydrogen carbonate, and saturated brine, which was dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain the title compound (13.0 mg, yield 78%). The NMR dataand ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.14 (t, J=7.1, 3H), 2.01 (pent, J=7.0,2H), 2.21 (t, J=7.5, 2H), 3.99 (q, J=7.1, 2H), 4.38 (t, J=6.7, 2H), 6.33(d, J=2.9, 1H), 7.41 (d, J=2.9, 1H), 7.76 (s, 1H), 11.86 (brs, 1H).ESI/MS m/e: 250.1 (M⁺+H, C₁₂H₁₅N₃O₃)

Example 46 Synthesis of ethyl4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (CompoundNo. 2502)

An N-iodosuccinimide (12.8 g) was added to a dichloromethane (350 mL)solution of ethyl 4-(4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(12.9 g), and stirred at room temperature overnight. A solid wasextracted by filtration, washed with diethylether, and then dried underreduced pressure, to obtain the title compound (11.8 g, yield 61%). Thefiltration solution was concentrated under reduced pressure, ethylacetate was added to the residue and vigorously stirred. The producedsolid was extracted by filtration, washed with ethyl acetate anddiethylether, and then dried under reduced pressure, to obtain the titlecompound (6.63 g, yield 34%). The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.13 (t, J=7.1, 3H), 2.02 (pent, J=7.0,2H), 2.22 (t, J=7.4, 2H), 3.96 (q, j=7.1, 2H), 4.39 (t, J=6.7, 2H), 7.63(s, 1H), 7.85 (s, 1H), 12.06 (brs, 1H). ESI/MS m/e: 376.0 (M⁺+H,C₁₇H₁₈IN₃O₃)

Example 47 Synthesis of ethyl4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2512)

The title compound was obtained by using an ethyl4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and3-pyridyl boric acid in a similar manner to that described in Example28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.11 (t, J=7.1, 3H), 2.09 (pent, J=7.0,2H), 2.29 (t, J=7.4, 2H), 3.96 (q, j=7.1, 2H), 4.45 (t, J=6.7, 2H), 7.41(m, 1H), 7.93 (s, 1H), 8.06 (s, 1H), 8.40 (m, 2H), 9.21 (m, 1H), 12.10(s, br, 1H). ESI/MS m/e: 327.0 (M⁺+H, C₁₇H₁₈N₄O₃)

Example 48 Synthesis of4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid(Compound No. 2503)

1M of aqueous lithium hydroxide solution (6.3 mL) was added to ethanol(24 mL) and water (3 mL) solution ofethyl-4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(0.78 g), and stirred at room temperature overnight. The solvent wasdistilled off under reduced pressure, and water (5 mL) was added to theresidue. 1M hydrochloric acid was added thereto to adjust pH to 4, and aproduced solid was extracted by filtration, which was dried underreduced pressure, to obtain the title compound (0.75 g, quantitativeyield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.07 (pent, J=7.0, 2H) 2.23 (t, J=7.3,2H), 4.46 (t, J=6.7, 2H), 7.77 (dd, J=4.3, J=8.2, 1H), 7.98 (s, 1H),8.24 (s, 1H), 8.58 (d, J=4.3, 1H), 8.79 (d, J=8.2, 1H), 9.39 (s, 1H),12.12 (brs, 1H), 12.24 (brs, 1H) ESI/MS m/e: 299.1 (M⁺+H, C₁₅H₁₄N₄O₃)

Example 49 Synthesis of4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-benzylbutanamide(Compound No. 2292)

A diisopropylethylamine (91 μL) and benzyl amine (29 μL) were added tosolution of N,N-dimethylformamide (4 mL) of4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (40mg). Further, O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (74 mg) was added thereto, and the mixture solutionwas stirred at room temperature overnight. The solvent was distilled offunder reduced pressure, and hot water was added to the residue. Aninsoluble portion was filtered off, the filtration solution wasconcentrated under reduced pressure, purified, to obtain the titlecompound (11. 6 mg, yield 22%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

The HPLC retention time: 5.1 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.12(m, 4H), 4.23 (d, J=6.0, 2H), 4.46 (t, J=6.3, 2H), 7.22 (m, 3H), 7.30(m, 2H), 7.73 (dd, J=5.0, J=8.2, 1H), 7.98 (s, 1H), 8.19 (s, 1H), 8.33(t, J=6.0, 1H), 8.56 (d, J=5.0, 1H), 8.74 (d, J=8.2, 1H), 9.37 (brs,1H), 12.22 (brs, 1H). ESI/MS m/e: 388.1 (M⁺+H, C₂₂H₂₁N₅O₂)

Example 50 Synthesis of ethyl4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2504)

An ethyl4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(1.72 g) was dissolved in dichloromethane (63 mL) by heating, and cooledto 0° C. 2 mol/L of surfuryl chloride/dichloromethane solution (7.9 mL)was added dropwise, and stirred at room temperature for 3 hours. Thesolvent was distilled off under reduced pressure, and dichloromethaneand saturated aqueous sodium hydrogen carbonate solution were added, andvigorously stirred. Two layers were separated, and the aqueous layer wasextracted with dichloromethane. The combined organic layer was washedwith saturated brine, and dried over sodium sulfate. The sodium sulfatewas filtered, and the solvent was distilled off under reduced pressureto obtain the title compound (1.89 g, quantitative yield). The NMR dataand ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm) 1.11 (t, J=7.1, 3H), 2.06 (pent, J=7.0,2H), 2.37 (t, J=7.2, 2H), 3.94 (q, J=7.1, 2H), 4.58 (t, J=6.7, 2H), 7.51(dd, J=4.7, J=7.9, 1H), 7.93 (d, J=3.0, 1H), 8.13 (dt, J=1.9, J=7.9,1H), 8.54 (d, J=7, 1H), 8.94 (s, 1H), 12.28 (brs, 1H). ESI/MS m/e: 361.1(M⁺+H, C₁₇H₁₇N₄O₃)

Example 51 Synthesis of4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoicacid (Compound No. 2505)

1M of aqueous lithium hydroxide solution (8.6 mL) was added to ethanol(25 mL) solution ofethyl-4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(1.24 g), and stirred at room temperature overnight. 1M of hydrochloricacid (8.6 mL) was added thereto, the solvent was distilled off underreduced pressure, to obtain the title compound as a mixture (1.73 g)with lithium chloride. The NMR data and ESI/MS data of the compound aregiven below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.02 (m, 2H), 2.29 (t, J=7.4, 2H), 4.57(t, J=6.9, 2H), 7.58 (ddd, J=0.8, J=4.9, J=8.0, 1H), 7.94 (s, 1H), 8.23(ddd, J=1.5, J=2.3, J=8.0, 1H), 8.57 (dd, J=1.5, J=4.9, 1H), 8.98 (dd,J=0.8, J=2.3, 1H), 12.16 (brs, 1H), 12.39 (brs, 1H). ESI/MS m/e: 333.1(M⁺+H, C₁₅H₁₃ClN₄O₃ LiCl)

Example 52 Synthesis of4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-(cyclohexylmethyl)butanamide(Compound No. 2264)

A cyclohexanemethylamine (27 mg) and diisopropyl-ethylamine (84 μL) wereadded to a solution of N,N-dimethylformamide (1 mL) of4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(40 mg). Further, O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (55 mg) was added thereto, and the mixture solutionwas stirred at room temperature for 2 hours. The reaction mixture wasseparated to ethyl acetate and aqueous layers. The organic layer waswashed with 1 mol/L of aqueous citric acid solution, saturated aqueoussodium hydrogen carbonate, and saturated brine, which was dried oversodium sulfate. The sodium sulfate was filtered off, and the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (5% methanol/ethyl acetate) to obtain thetitle compound (35 mg, yield 68%). The HPLC retention time, NMR data andESI/MS data of the compound are given below.

The HPLC retention time: 7.2 (min) ¹H-NMR (400 MHz, CD₃OD)δ(ppm): 0.09(m, 2H), 1.21 (m, 3H), 1.42 (m, 1H), 1.69 (m, 5H), 2.16 (m, 2H), 2.29(t, H=7.4, 2H), 2.95 (d, J=7.0, 2H), 4.66 (t, J=6.9, 2H), 7.53 (ddd,J=0.9, J=5.0, J=8.0, 1H), 7.89 (s, 1H), 8.22 (ddd, J=1.6, J=2.2, J=8.0,1H), 8.49 (dd, J=1.6, J=5.0, 1H), 8.93 (dd, J=0.9, J=2.2, 1H). ESI/MSm/e: 428.2 (M⁺+H, C₂₂H₂₆ClN₅O₂)

Example 53 Synthesis of4-[6-(3,4-dimethoxyphenyl)-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-(cyclohexylmethyl)butanamide(Compound No. 2269)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of4-(6-chloro-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-(cyclohexylmethyl)butanamide(50 mg), 3,4-dimethoxyphenyl boric acid (64 mg), and potassium acetate(57 mg) was subjected to deaeration, followed by flushing with nitrogengas. A small amount of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloro-methane (1:1) complex body was added thereto. Thereaction mixture was heated at 140° C. for 30 minutes by usingmicrowave. The solvent was distilled off under reduced pressure and theresidue was purified by column chromatography on silica gel (5-8%methanol/ethyl acetate), and further purified by fraction HPLC to obtainthe title compound (12 mg, yield 16%). The HPLC retention time, NMR dataand ESI/MS data of the compound are given below.

HPLC retention time: 8.0 (min) ¹H-NMR (400 MHz, CD₃OD)δ(ppm): 0.85 (m,2H), 1.19 (m, 3H) 1.35 (m, 1H), 1.66 (m, 5H), 2.01 (m, 2H), 2.13 (t,J=7.4, 2H), 2.88 (d, J=6.8, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 4.42 (t,J=7.5, 2H), 7.00 (dd, J=2.0, J=8.1, 1H), 7.03 (d, J=2.0, 1H), 7.13 (d,J=8.1, 1H), 7.81 (dd, J=5.6, J=8.2, 1H), 7.99 (s, 1H), 8.39 (ddd, J=1.4,J=2.1, J=8.2, 1H), 8.52 (d, J=5.6, 1H), 8.90 (d, J=2.1, 1H). ESI/MS m/e:530.3 (M⁺+H, C₃₀H₃₅N₅O₄)

Example 54 Synthesis of ethyl4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

A sodium hydride (521 mg) was added to solution of N,N-dimethylformamide(60 mL) of ethyl4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (4.07 g)in a small amount by each, and the mixture solution was stirred at roomtemperature for 30 minutes. A benzylchloromethylether (2.04 g) was addeddropwise, and the mixture solution was further stirred for 2 hours. Thesolvent was distilled off under reduced pressure to separate the residueto ethyl acetate and aqueous layers. The organic layer was washed withwater and saturated brine, and dried over sodium sulfate. The sodiumsulfate was filtered off, and the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (15-30% ethyl acetate/cyclohexane), to obtain the titlecompound (3.80 g, yield 71%). The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (400 MHz, CDCl₃)δ(ppm): 1.25 (t, J=7.1, 3H), 2.18 (pent, J=7.0,2H), 2.32 (t, J=7.2, 2H), 4.12 (q, J=7.1, 2H), 4.51 (t, J=6.9, 2H), 4.65(s, 2H), 5.50 (s, 2H), 7.22 (s, 1H), 7.29 (m, 1H), 7.33 (m, 4H), 8.03(s, 1H). ESI/MS m/e: 496.1 (M⁺+H, C₂₀H₂₂IN₃O₄)

Example 55 Synthesis ofethyl-4-{7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

The title compound was obtained by using ethyl4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoateand 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazolin a similar manner to that in Example 28. The NMR data and ESI/MS dataof the compound are given below.

¹H-NMR (400 MHz, CD₃OD)δ(ppm): 1.16 (t, J=7.1, 3H), 2.16 (pent, J=7.0,2H), 2.33 (t, J=7.2, 2H), 3.92 (s, 3H), 3.02 (q, J=7.1, 2H), 4.49 (t,J=6.7, 2H), 4.68 (s, 2H), 5.56 (s, 2H), 7.22 (m, 1H), 7.28 (m, 2H), 7.33(m, 2H), 7.54 (s, 1H), 7.86 (d, J=0.6, 1H), 8.03 (s, 1H), 8.10 (s, 1H).ESI/MS m/e: 450.3 (M⁺+H, C₂₄H₂₇N₅O₄)

Example 56 Synthesis of4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoicacid (Compound No. 2506)

Solution of concentrated hydrochloric acid (3 mL) ofethyl-4-{6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoatewas heated for 1 hour to reflux. The solvent was distilled off underreduced pressure, and methanol solution (3 mL) of 2 mol/L ammonia wasadded to the residue. The solvent was distilled off under reducedpressure, and 1 mol/L of aqueous citric acid solution was added to theresidue. A produced solid was extracted by filtration, washed with waterand diethylether, and then dried under reduced pressure, to obtain thetitle compound (133 mg, yield 87%). The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.97 (pent, J=7.0, 2H), 2.23 (t, J=7.4,2H), 3.91 (s, 3H), 4.50 (t, J=6.8, 3H), 7.91 (d, J=3.6, 1H), 8.04 (s,1H), 8.24 (s, 1H), 12.11 (s, 1H), 12.17 (d, J=3.6, 1H). ESI/MS m/e:336.2 (M⁺+H, C₁₄H₁₄ClN₅O₃)

Example 57 Synthesis of4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]]-N-[(4-methylphenyl)methyl]butanamide(Compound No. 2507)

A 4-methylbenzyl amine (29 mg) and a diisopropylethylamine (84 μm) wereadded to a solution of an N,N-dimethylformamide (1 mL) of4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-butanoate(40 mg). An O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (55 mg) was further added, and the mixture solutionwas stirred at room temperature overnight. An ethyl acetate and 1 mol/Lof an aqueous citric acid solution were added to the reaction mixture,and separated to two layers. The organic layer was washed with saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over sodium sulfate. The sodium sulfate was filtered off, and thesolvent was distilled off under reduced pressure, to obtain the titlecompound (67 mg, quantitative yield). The compound was not furtherpurified, but used for the following reaction. The ESI/MS data of thecompound is given below.

ESI/MS m/e: 439.2 (M⁺+H, C₂₂H₂₃ClN₆O₂)

Example 58 Synthesis of4-[6-(3,4-dimethoxyphenyl)-7-(1-methylpyrazol-4-yl)-4-oxo-7-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl]butanamide(Compound No. 2345)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl]butanamide(65 mg), 3,4-dimethoxyphenyl boric acid (81 mg), and potassium acetate(73 mg) was subjected to deaeration, followed by flushing with nitrogengas. A small amount of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloro-methane (1:1) complex body was added thereto. Thereaction mixture was heated at 160° C. for 45 minutes by usingmicrowaves. The solvent was distilled off under reduced pressure and theresidue was purified by column chromatography on silica gel (5-8%methanol/ethyl acetate), and further purified by fraction HPLC to obtainthe title compound (4.4 mg, yield 7%). The HPLC retention time, NMR dataand ESI/MS data of the compound are given below.

HPLC retention time: 8.2 (min) ¹H-NMR (400 MHz, CD₃OD)δ(ppm): 1.98 (m,2H), 2.13 (t, J=7.5, 2H), 2.29 (2, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 3.91(s, 3H), 4.18 (s, 2H), 4.36 (t, J=7.4, 2H), 6.98 (m, 2H), 7.07 (m, 4H),7.12 (d, J=7.9, 1H), 7.28 (2, 1H), 7.66 (s, 1H), 7.97 (2, 1H). ESI/MSm/e: 541.1 (M⁺+H, C₃₀H₃₂N₆O₄)

Example 59 Synthesis ofethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2508)

The title compound was obtained by usingethyl-4-[3-amino-5-cyclopropyl-2-(ethoxycarbonyl)pyrolyl]butanoatehydrochloride in a similar manner to that in Example 45. The NMR dataand ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.74 (m, 2H), 1.00 (m, 2H) 1.13 (t,J=7.2, 3H), 1.93-2.06 (m, 3H), 2.31 (t, J=7.4, 2H), 3.98 (dd, J=7.2,J=14.2, 2H), 4.52 (t, J=7.0, 2H), 6.00 (s, 1H), 7.71 (s, 1H), 11.76(brs, 1H). ESI/MS m/e: 290.2 (M⁺+H, C₁₅H₁₉N₃O₃)

Example 60 Synthesis ofethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2509)

A dichloromethane (40 mL) solution of anethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(1.58 g) and an N-iodosuccinimide (1.35 g) was stirred at roomtemperature for 2 hours. Water was added, and the mixture solution wasfurther stirred for 30 minutes. A solid was extracted by filtration,washed by water and ethyl acetate, and dried under reduced pressure, toobtain the title compound (1.82 g, yield 80%). The filtration solutionwas separated to ethyl acetate and aqueous layers, and the aqueous layerwas extracted with ethyl acetate. The combined organic layer was washedwith saturated brine, and dried over a magnesium sulfate. The magnesiumsulfate was filtered off, and the solvent was distilled off underreduced pressure. A produced solid was extracted by filtration, washedwith ethyl acetate, and dried under reduced pressure, to obtain thetitle compound (0.35 mg, yield 15%). The NMR data and ESI/MS data of thecompound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.89 (m, 2H), 1.08-1.15 (m, 5H), 1.80(m, 1H), 2.01 (m, 2H), 2.31 (t, J=7.3, 2H), 3.96 (dd, J=7.0, J=14.3,2H), 4.57 (t, J=7.2, 2H), 7.82 (s, 1H), 12.00 (brs, H). ESI/MS m/e:416.1 (M⁺+H, C₁₅H₁₈IN₃O₃)

Example 61 Synthesis ofethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2510)

The title compound was obtained by usingethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoateand 3-pyridyl boric acid in a similar manner to that in Example 28. TheNMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.31 (m, 2H), 1.01 (m, 2H) 1.13 (t,J=7.2, 3H), 2.06-2.13 (m, 3H), 2.40 (t, J=7.3, 2H), 3.98 (dd, J=7.2,J=14.2, 2H), 4.61 (t, J=7.2, 2H), 7.43 (ddd, J=0.8, J=4.8, J=7.9, 1H),7.82 (s, 1H), 8.01 (dt, J=2.0, J=8.1, 1H), 8.46 (dd, J=1.7, J=4.7, 1H),8.83 (dd, J=0.8, J=2.3, 1H), 11.99 (brs, 1H). ESI/MS m/e: 367.2 (M⁺+H,C₂₀H₂₂N₄O₃)

Example 62 Synthesis of4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoicacid (Compound No. 2363) hydrochloride

1M of aqueous lithium hydroxide solution (7.3 mL) was added to dioxane(25 mL) and water (10 mL) solution ofethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(1.06 g), and stirred at room temperature for 3 hours. 1M hydrochloricacid (10.2 mL) was added dropwise, and the solvent was distilled offunder reduced pressure. An ethanol was added to a residue, a solid wasextracted by filtration, washed with ethanol, and dried under reducedpressure, to obtain the title compound (1.10 g, quantitative yield). TheNMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.39 (m, 2H), 1.10 (m, 2H) 2.07 (m,2H), 2.18 (m, 1H), 2.33 (t, J=7.4, 2H), 4.63 (t, J=7.3, 2H), 7.95 (s,1H), 8.10 (dd, J=5.7, J=8.1, 1H), 8.82 (m, 2H), 9.16 (d, J=1.8, 1H),12.26 (brs, 1H). ESI/MS m/e: 339.0 (M⁺+H, C₁₈H₁₈N₄O₃HCl)

Example 63 Synthesis of4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-[(4-methylphenyl)methyl]butanamide(Compound No. 2331)

A diisopropylethylamine (70 μL) and a 4-methylbenzyl amine (15 mg) wereadded to solution of N,N-dimethylformamide (1.5 mL) of4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(30 mg) and O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (46 mg). The reaction solution was stirred at roomtemperature for 4 hours. The solvent was distilled off under reducedpressure, and ethyl acetate and water were added to a residue, separatedto two layers, and an aqueous layer was extracted with ethyl acetate.The combined organic layer was dried over a sodium sulfate. The sodiumsulfate was filtered off, and the solvent was distilled off underreduced pressure. The residue was purified by fraction HPLC, to obtainthe title compound (3.1 mg, yield 9%). The HPLC retention time, NMR dataand ESI/MS data of the compound are given below.

The HPLC retention time: 7.3 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.27(m, 2H), 0.93 (m, 2H), 2.01-2.11 (m, 3H), 2.21-2.27 (m, 5H), 4.21 (d,J=5.9, 2H), 4.58 (t, J=7.1, 2H), 7.10-7.15 (m, 4H), 7.43 (ddd, J=0.8,J=4.8, J=7.9, 1H), 7.82 (s, 1H), 8.01 (dt, J=2.0, J=8.1, 1H), 8.34 (t,J=5.9, 1H), 8.46 (dd, J=1.8, J=4.8, 1H), 8.84 (dd, J=0.8, J=2.3, 1H).ESI/MS m/e: 442.2 (M⁺+H, C₂₆H₂₇N₅O₂)

Example 64 Synthesis ofethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(Compound No. 2511)

The title compound was obtained by usingethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoateand 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazolin a similar manner to that in Example 28. The NMR data and ESI/MS dataof the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.51 (m, 2H), 1.13 (m, 5H), 1.91 (m,1H), 2.03 (m, 2H), 2.31 (t, J=7.3, 2H), 3.89 (s, 3H), 3.97 (dd, J=7.2,J=14.2, 2H), 4.58 (t, J=7.0, 2H), 7.80 (d, J=3.3, 1H), 7.83 (d, J=0.7,1H), 8.03 (s, 1H), 11.87 (brs, 1H). ESI/MS m/e: 370.2 (M⁺+H,C₁₉H₂₃N₅O₃)]

Example 65 Synthesis of4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoicacid (Compound No. 2364)

1M of aqueous lithium hydroxide solution (3.5 mL) was added todioxane/water (4/1) solution (25 mL) ofethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate(0.52 g) dropwise. The reaction solution was stirred at room temperaturefor 4 hours, and 1M hydrochloric acid (3.5 mL) was added theretodropwise. The solvent was distilled off under reduced pressure, aresidue was purified by column chromatography on silica gel(dichloromethane/methanol/acetate/water=240/30/3/2), a diethylether wasadded to the obtained solid, and finely pulverized. The solid wasextracted by filtration, washed with diethylether, and dried underreduced pressure, to obtain the title compound (0.40 g, yield 84%). TheNMR data and ESI/MS data of the compound are given below.

¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.51 (m, 2H), 1.12 (m, 2H), 1.88-2.02(m, 3H), 2.23 (t, J=7.4, 2H), 3.89 (s, 3H), 4.57 (t, J=7.2, 2H), 7.80(d, J=3.5, 1H), 7.83 (d, J=0.7, 1H), 8.03 (s, 1H), 11.87 (brs, 1H).ESI/MS m/e: 342.2 (M⁺+H, C₁₇H₁₉N₅O₃)

Example 66 Synthesis of4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl]butanamide(Compound No. 2332)

A diisopropylethylamine (78 μL) and a 4-methylbenzyl amine (13 mg) wereadded to a solution of N,N-dimethylformamide (1.0 mL) of4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoate(30 mg) and O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (40 mg). The reaction solution was stirred at roomtemperature overnight. The solvent was distilled off under reducedpressure, a residue was purified by fraction HPLC, to obtain the titlecompound (30 mg, yield 77%). The HPLC retention time and ESI/MS data ofthe compound are given below.

The HPLC retention time: 8.0 (min) ESI/MS m/e: 445.3 (M⁺+H, C₂₅H₂₈N₆O₂)

Example 67 Synthesis of5-benzyl-7-(1-oxy(3-pyridyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one(Compound No. 2499)

30% aqueous hydrogen peroxide solution (92 mg) was added to an aceticacid (2 mL) solution of5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (31 mg), andthe solution mixture was stirred at room temperature overnight. Thereaction mixture was cooled to room temperature, purified by fractionHPLC, to obtain the title compound (19 mg, yield 58%). The HPLCretention time, NMR data and ESI/MS data of the compound are givenbelow.

The HPLC retention time: 5.8 (min) ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 5.64(s, 2H), 7.24-7.35 (m, 5H), 7.46 (m, 1H), 8.00 (m, 2H), 8.10 (m, 1H),8.34 (s, 1H), 9.11 (s, 1H), 12.25 (brs, 1H). ESI/MS m/e: 319.3 (M⁺+H,C₁₈H₁₄N₄O₂)

Example 68 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(5-methyl(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 2126)

A(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylaminehydrochloride and a diisopropylethylamine (100 mg) were added thereto,and the solution mixture was stirred overnight under overheat reflux.The solvent was distilled off under reduced pressure, a dichloromethane(2.5 mL) and water (2.5 mL) were added thereto, and an organic layer wasfractionally extracted. An aqueous layer was further extracted withdichloromethane (2.5 mL), an organic layer was combined, dried oversodium sulfate, and the solvent was distilled off under reducedpressure, to obtain a residue (113 mg). This residue was dissolved indichloromethane (2 mL), acetate (18 mg),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (57 mg),and triethylamine (41 μL) were added thereto, and the solution mixturewas stirred at 40° C. for 1 hour. The reaction solution wasconcentrated, and purified by fraction HPLC, to obtain the titlecompound (7.2 mg, yield 6%). The HPLC retention time and ESI/MS data ofthe compound are given below.

The HPLC retention time: 9.5 (min) ESI/MS m/e: 476.9 (M⁺+H,C₂₀H₂₁ClN₆O₄S)

Example 69 Synthesis of(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 2513)

A(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylaminehydrochloride and a diisopropylethylamine (100 mg) were added thereto,and the solution mixture was stirred overnight under overheat reflux.The solvent was distilled off under reduced pressure, a dichloromethane(2.5 mL) and water (2.5 mL) were added thereto, and an organic layer wasfractionally extracted. An aqueous layer was further extracted withdichloromethane (2.5 mL), an organic layer was combined, dried oversodium sulfate, and the solvent was distilled off under reducedpressure, to obtain a residue (113 mg). Meanwhile N,N-dimethylformamide(40 mg) was dissolved in diethylether (1 mL), phosphorus oxychloride (84mg) was added thereto, and the solution mixture was stirred at roomtemperature for 1 hour, to obtain an oily compound. The produced oilycompound was washed with diethylether (1 mL) twice, and suspended to asolvent mixture (3 mL) of 1,4-dioxane and diethylether. This suspensionwas added to the residue, and stirred at room temperature for 2 hours.The reaction solution was concentrated, water (5 mL) and ethyl acetate(5 mL) were added thereto, and an organic layer was separated. Anaqueous layer was further extracted with ethyl acetate (5 mL), anorganic layer was combined and concentrated, and then purified byfraction HPLC, to obtain the title compound (1.9 mg, yield 1.6%). TheHPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time: 9.1 (min) ESI/MS m/e: 462.9 (M⁺+H, C₁₉H₁₉ClN₆O₄S)

Example 70 Synthesis of(t-butoxy)-N-{2-[6-(3-hydroxyphenyl)-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide(Compound No. 2121)

At-butoxy)-N-(2-{4-oxo-6-[3-(phenylmethoxy)phenyl]-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}ethyl}carboxyamide(8.0 mg) was dissolved in ethanol, and palladium carbon (20 mg) wasadded thereto. The reaction system was substituted by hydrogen, andstirred at 60° C. overnight under atmospheric hydrogen pressure. Thereaction solution was cooled to room temperature, and the palladiumcarbon was filtered off. The filtration solution was concentrated,purified by fraction HPLC, to obtain the title compound (4.0 mg, yield60%). The HPLC retention time and ESI/MS data of the compound are givenbelow.

HPLC retention time: 6.3 (min) ESI/MS m/e: 448.0 (M⁺+H, C₂₄H₂₅N₅O₄)

Examples 71 to 494

The following compounds of the present invention were synthesizedaccording to any method of Example 1 to Example 70 by usingcorresponding starting materials and reaction agents. The ESI/MS data inthe HPLC/mass spectrum analysis, the retention time of the compound inthe HPLC analysis and purity under the following analysis conditions ofeach compound, and compound numbers corresponding to executed synthesesare summarized in Table 2. Compound numbers in the table representcompound numbers of Table 1 listed as the preferred specific examples.

TABLE 2 Compound ESI/MS HPLC Purity Ex. no. no. Formula m/e min (%)Synthesis 71 19 C₁₉H₂₁N₅O₂ 352.2 5.7 96 Ex. 40 72 27 C₂₆H₂₅N₅O₃ 456.37.8 99 Ex. 40 73 29 C₁₇H₁₇N₅O₂ 324.2 3.3 99 Ex. 40 74 40 C₂₁H₁₅Cl₂N₇OS484.2 7.7 98 Ex. 38 75 80 C₂₀H₁₄BrClN₆OS 503.2 6.8 100 Ex. 38 76 83C₂₆H₁₉ClN₆S₂ 515.4 10.4 96 Ex. 38 77 212 C₁₉H₁₄ClN₅OS 395.4 11.7 86 Ex.28 78 219 C₂₀H₁₈ClN₅O₂S 428.0 5.6 95 Ex. 35 79 230 C₂₁H₂₀ClN₅O₂S 442.46.5 100 Ex. 37 80 245 C₂₁H₂₀ClN₅O₂S 442.0 6.1 94 Ex. 35 81 254C₂₂H₂₂ClN₅O₂S 456.1 6.9 95 Ex. 35 82 257 C₂₁H₂₃N₅O₂ 378.2 4.3 100 Ex. 3683 263 C₂₀H₂₁N₅O₂ 364.2 10.0 96 Ex. 35 84 269 C₂₁H₁₈ClN₅O₂S 440.4 6.2100 Ex. 37 85 280 C₂₂H₂₅N₅O₂ 392.2 5.4 100 Ex. 35 86 287 C₂₃H₂₂ClN₅O₂S468.0 7.1 95 Ex. 35 87 288 C₂₂H₂₁ClN₄O₂S₂ 472.9 11.8 97 Ex. 35 88 297C₂₃H₂₇N₅O₂ 406.2 12.9 98 Ex. 35 89 303 C₂₄H₂₄ClN₅O₂S 482.4 8.8 100 Ex.37 90 321 C₁₉H₁₃ClF₃N₅O₂S 468.4 7.3 99 Ex. 37 91 330 C₂₃H₂₁N₅O₂ 400.55.0 99 Ex. 35 92 347 C₂₅H₁₈ClFN₄OS₂ 509.4 15.0 99 Ex. 37 93 348C₂₄H₁₇ClFN₅O₂S 494.2 8.0 100 Ex. 37 94 361 C₂₆H₂₀ClN₅O₄S 534.0 9.4 78Ex. 35 95 370 C₂₀H₁₃BrClF₃N₄O₃S 563.1 10.4 100 Ex. 35 96 492C₂₃H₂₃ClN₆O₂S 483.1 10.8 93 Ex. 33 97 504 C₂₄H₂₅ClN₆O₂S 497.5 8.6 84 Ex.33 98 536 C₃₀H₂₇ClN₆O₃S 587.4 9.0 79 Ex. 33 99 595 C₂₁H₂₅N₅O₂ 380.2 5.2100 Ex. 35 100 596 C₂₂H₂₂ClN₅O₂S 456.1 6.9 98 Ex. 35 101 601 C₂₁H₂₅N₅O₂380.2 5.3 100 Ex. 35 102 602 C₂₂H₂₂ClN₅O₂S 456.1 7.1 94 Ex. 35 103 605C₂₂H₂₉N₅O₂ 396.3 5.1 100 Ex. 35 104 615 C₂₂H₂₇N₅O₂ 394.1 7.5 99 Ex. 35105 616 C₂₁H₂₆N₄O₃ 383.2 10.3 78 Ex. 28 106 617 C₂₁H₂₆N₄O₂S 399.1 11.687 Ex. 35 107 618 C₂₀H₂₆N₆O₂ 383.2 8.1 60 Ex. 28 108 627 C₂₂H₂₃ClN₄O₃S459.3 15.0 95 Ex. 35 109 628 C₂₂H₂₃ClN₄O₂S₂ 475.2 15.7 100 Ex. 35 110634 C₂₂H₂₇N₅O₂ 394.2 5.7 100 Ex. 53 111 641 C₂₃H₂₇N₅O₂ 406.2 5.9 100 Ex.35 112 646 C₂₄H₂₄ClN₅O₂S 482.0 6.9 95 Ex. 35 113 657 C₂₁H₂₃N₅O₂ 378.34.3 97 Ex. 35 114 659 C₂₂H₂₀ClN₅O₂S 454.1 6.5 94 Ex. 35 115 664C₂₃H₂₄ClN₅O₂S 470.2 9.1 99 Ex. 35 116 667 C₂₄H₂₉N₅O₂ 420.2 6.3 100 Ex.36 117 668 C₂₅H₂₆ClN₅O₂S 496.0 8.3 8.5 80 Ex. 36 118 668 C₂₅H₂₆ClN₅O₂S496.0 8.3 89 Ex. 36 119 673 C₂₅H₂₆ClN₅O₃S 512.0 6.6 98 Ex. 36 6.9 120678 C₂₈H₃₂ClN₅O₂S 538.1 11.1 97 Ex. 36 121 689 C₂₅H₂₅ClN₆O₃S 525.0 5.978 Ex. 36 122 694 C₂₄H₂₉N₅O₂ 420.2 6.6 100 Ex. 35 123 696 C₂₅H₂₆ClN₅O₂S496.0 8.5 98 Ex. 35 124 702 C₁₉H₂₁N₅O₃ 368.2 9.5 82 Ex. 35 125 704C₂₀H₁₈ClN₅O₃S 444.0 5.4 87 Ex. 35 126 709 C₂₁H₂₁ClN₆O₂S 457.1 4.8 94 Ex.35 127 713 C₂₁H₁₉ClN₆O₃S 471.0 5.2 85 Ex. 36 128 718 C₂₂H₂₀ClN₅O₄S 486.06.0 90 Ex. 35 129 723 C₂₄H₂₃N₅O₂ 414.5 5.0 98 Ex. 35 130 724C₂₅H₂₀ClN₅O₂S 490.4 8.1 100 Ex. 37 131 729 C₂₅H₂₀ClN₅O₃S 506.0 8.0 90Ex. 35 132 733 C₂₅H₂₅N₅O₂ 428.0 6.7 98 Ex. 35 133 734 C₂₆H₂₂ClN₅O₂S504.0 8.5 94 Ex. 35 134 741 C₂₂H₂₀ClN₅O₂S 454.0 5.7 87 Ex. 35 135 760C₂₀H₂₄N₆O₂ 381.1 5.1 98 Ex. 32 136 768 C₂₁H₂₁ClN₆O₂S 457.1 5.4 95 Ex. 32137 770 C₂₀H₂₀ClN₅O₂S₂ 461.9 10.9 99 Ex. 32 138 776 C₂₄H₂₅ClN₆O₂S 497.07.7 95 Ex. 32 139 785 C₂₃H₂₂N₆O₂ 415.0 6.9 96 Ex. 32 140 795C₂₃H₁₈ClN₅O₂S₂ 495.9 12.1 99 Ex. 32 141 801 C₂₄H₁₈ClFN₆O₂S 508.9 7.9 97Ex. 32 142 802 C₂₄H₁₈ClFN₆O₂S 508.9 8.1 85 Ex. 32 143 803 C₂₄H₁₈Cl₂N₆O₂S526.9 9.1 95 Ex. 32 144 804 C₂₅H₂₁ClN₆O₃S 520.9 7.7 98 Ex. 32 145 805C₂₅H₂₁ClN₆O₂S 504.9 7.9 95 Ex. 32 146 806 C₂₅H₂₁ClN₆O₂S 504.9 8.2 85 Ex.32 147 807 C₂₅H₂₁ClN₆O₂S 504.9 8.1 89 Ex. 32 148 808 C₂₄H₁₈Cl₂N₆O₂S520.8 9.3 97 Ex. 32 149 809 C₂₄H₁₈Cl₂N₆O₂S 526.9 8.7 96 Ex. 32 150 810C₂₄H₁₈ClFN₆O₂S 508.9 7.7 96 Ex. 32 151 811 C₂₅H₂₁ClN₆O₃S 520.9 8.9 93Ex. 32 152 812 C₂₅H₂₁ClN₆O₃S 520.9 7.4 99 Ex. 32 153 912 C₂₂H₂₆N₄O₃349.5 9.5 91 Ex. 28 154 915 C₂₁H₂₅N₅O₃ 396.3 5.5 98 Ex. 28 155 917C₂₀H₂₄N₄O₄ 385.3 10.9 66 Ex. 28 156 918 C₂₀H₂₄N₄O₃S 401.5 12.4 93 Ex. 28157 948 C₁₈H₂₁ClN₄O₃S 409.2 11.4 82 Ex. 26 158 956 C₂₄H₂₅ClN₄O₃S 485.213.9 91 Ex. 26 159 968 C₂₃H₂₉ClN₄O₃S 477.3 12.9 95 Ex. 28 160 970C₁₉H₁₉ClN₄O₃S 419.3 10.9 98 Ex. 27 161 972 C₂₃H₂₇ClN₄O₃S 475.2 11.4 83Ex. 27 162 973 C₂₅H₃₀ClN₅O₃S 499.2 7.7 81 Ex. 27 163 974 C₂₅H₂₃ClN₄O₃S495.5 10.9 98 Ex. 27 164 975 C₂₅H₂₂ClFN₄O₃S 513.2 11.1 95 Ex. 27 165 976C₂₆H₂₅ClN₄O₄S 525.2 11.0 98 Ex. 27 166 977 C₂₅H₂₄ClN₅O₃S 510.2 7.9 28Ex. 27 167 978 C₂₅H₂₂Cl₂N₄O₃S 529.2 11.5 95 Ex. 27 168 979 C₂₄H₂₂ClN₅O₃S496.2 7.9 72 Ex. 27 169 980 C₂₄H₃₀ClN₅O₃S 487.3 7.5 92 Ex. 27 170 982C₂₂H₂₇ClN₄O₃SSi 491.4 12.0 87 Ex. 27 171 983 C₂₃H₂₃ClN₄O₃S 471.3 10.5 92Ex. 28 172 984 C₂₃H₂₂ClFN₄O₃S 489.2 10.9 85 Ex. 28 173 985C₂₄H₂₂ClF₃N₄O₃S 539.2 12.1 92 Ex. 28 174 986 C₂₄H₂₂ClF₃N₄O₄S 555.3 12.293 Ex. 28 175 987 C₂₃H₂₂Cl₂N₄O₃S 505.1 11.6 95 Ex. 28 176 988C₂₅H₂₅ClN₄O₄S 513.3 9.8 88 Ex. 28 177 989 C₂₉H₂₇ClN₄O₄S 563.3 12.5 91Ex. 28 178 990 C₂₅H₂₇ClN₄O₅S 531.3 9.5 91 Ex. 28 179 991 C₂₅H₂₈ClN₅O₃S514.2 7.3 79 Ex. 28 180 992 C₂₄H₂₅ClN₄O₃S 485.3 11.1 94 Ex. 28 181 993C₂₇H₂₅ClN₄O₃S 521.6 — 81 Ex. 28 182 994 C₂₅H₂₇ClN₄O₃S 499.2 11.6 96 Ex.28 183 995 C₂₁H₂₁ClN₆O₃S 473.2 8.0 22 Ex. 28 184 996 C₂₆H₂₈ClN₅O₄S 542.38.7 90 Ex. 28 185 997 C₂₉H₃₃ClN₄O₃S 553.3 14.0 88 Ex. 28 186 998C₂₂H₂₂ClN₅O₃S 472.2 6.6 78 Ex. 28 187 999 C₂₂H₂₂ClN₅O₃S 472.4 8.0 97 Ex.28 188 1001 C₂₁H₂₁ClN₄O₄S 461.1 12.5 84 Ex. 28 189 1002 C₂₁H₂₁ClN₄O₃S₂477.1 13.1 94 Ex. 28 190 1003 C₂₃H₂₄ClN₅O₄S 502.0 11.1 61 Ex. 28 1911004 C₂₃H₂₄ClN₅O₄S 502.0 11.5 71 Ex. 28 192 1005 C₂₃H₂₄ClN₅O₄S 502.1 7.793 Ex. 28 193 1006 C₂₂H₂₁Cl₂N₅O₃S 506.0 12.8 90 Ex. 28 194 1007C₂₂H₂₁ClFN₅O₃S 490.1 12.1 80 Ex. 28 195 1008 C₂₂H₂₁ClFN₅O₃S 490.1 12.894 Ex. 28 196 1009 C₂₆H₂₄ClN₅O₃S 522.0 10.4 54 Ex. 28 197 1010C₂₄H₂₂ClN₅O₃S 496.4 14.7 88 Ex. 28 198 1011 C₂₃H₂₂ClFN₄O₃S 489.3 13.0 99Ex. 28 199 1012 C₂₃H₂₂ClFN₄O₃S 489.4 13.3 96 Ex. 28 200 1013C₂₂H₂₃ClN₄O₃S₂ 491.3 12.9 99 Ex. 28 201 1014 C₂₀H₂₁ClN₆O₃S 461.4 8.9 98Ex. 28 202 1106 C₁₈H₁₉N₅O₂ 338.4 5.1 97 Ex. 40 203 1131 C₁₅H₁₅N₅O₂ 298.32.2 99 Ex. 40 204 1132 C₁₄H₁₃N₅O₂ 284.2 1.7 99 Ex. 40 205 1146C₁₆H₁₅N₅O₂ 310.4 2.6 99 Ex. 40 206 1161 C₁₉H₁₅N₅O₂ 346.2 5.9 96 Ex. 40207 1168 C₁₉H₂₃N₅O₂ 354.3 7.1 99 Ex. 40 208 1170 C₁₅H₁₄N₄O₃ 299.2 4.4 96Ex. 39 209 1174 C₁₂H₁₀N₄O 227.2 2.4 100 Ex. 28 210 1175 C₁₂H₉ClN₄O 261.14.4 95 Ex. 41 211 1177 C₁₁H₈N₄O 213.1 5.0 99 Ex. 28 212 1179 C₁₈H₁₄N₄O303.2 7.2 99 Ex. 39 213 1181 C₁₉H₁₅N₇O 358.1 3.6 100 Ex. 38 214 1182C₂₃H₁₆ClN₇OS 474.0 6.8 67 Ex. 38 215 1183 C₂₂H₁₇ClN₈OS 477.1 7.7 100 Ex.38 216 1184 C₂₃H₁₉N₇O 410.3 2.3 100 Ex. 38 217 1185 C₂₄H₁₈ClN₇OS 487.96.0 90 Ex. 38 218 1186 C₂₂H₁₇ClF₃N₇OS 520.1 8.1 100 Ex. 38 219 1206C₂₀H₁₉ClN₆O₂S 443.1 6.7 97 Ex. 35 220 1216 C₂₁H₂₁ClN₆O₂S 457.0 8.6 87Ex. 8 221 1217 C₂₂H₂₃ClN₆O₂S 471.1 7.6 83 Ex. 35 222 1228 C₂₃H₂₅ClN₆O₂S485.2 8.2 96 Ex. 35 223 1236 C₂₅H₂₆ClN₅O₂S 497.9 8.4 96 Ex. 36 224 1237C₂₄H₂₇ClN₆O₂S 499.2 8.5 99 Ex. 36 225 1243 C₂₅H₂₂ClFN₆O₂S 525.2 8.5 95Ex. 35 226 1250 C₂₁H₂₃ClN₆O₂S 459.2 7.5 95 Ex. 35 227 1257 C₂₁H₂₃ClN₆O₂S459.2 7.6 98 Ex. 35 228 1258 C₁₈H₂₄N₆O₂ 357.2 5.9 100 Ex. 53 229 1259C₁₈H₂₃ClN₆O₂ 391.2 6.7 98 Ex. 50 230 1260 C₂₁H₂₇N₅O₂ 382.2 5.3 100 Ex.53 231 1261 C₂₀H₂₈N₆O₂ 385.3 6.4 96 Ex. 35 232 1262 C₂₁H₃₀N₆O₂ 399.3 6.6100 Ex. 35 233 1271 C₂₁H₂₈N₆O₂ 397.2 5.8 100 Ex. 35 234 1277 C₂₃H₂₈N₆O₃437.3 7.6 79 Ex. 53 235 1278 C₂₂H₂₆N₆O₃ 423.2 7.2 100 Ex. 53 236 1282C₂₃H₂₅N₅O₂S 436.2 6.0 95 Ex. 53 237 1284 C₂₂H₂₆N₆O₂S 439.2 7.5 100 Ex.53 238 1286 C₂₃H₂₈N₆O₂S 453.2 8.0 100 Ex. 53 239 1287 C₂₃H₂₄ClN₅O₃S486.3 6.7 100 Ex. 67 240 1288 C₂₂H₂₅ClN₆O₂S 473.1 7.8 93 Ex. 35 241 1293C₂₃H₂₇ClN₆O₂S 487.1 8.6 100 Ex. 28 242 1296 C₂₃H₂₈N₆O₂S 453.2 8.1 95 Ex.53 243 1297 C₂₁H₂₅N₅O₂ 380.2 5.2 96 Ex. 53 244 1331 C₂₃H₂₇N₇O₂ 434.2 5.2100 Ex. 53 245 1332 C₂₂H₂₈N₈O₂ 437.3 5.9 100 Ex. 53 246 1333 C₂₆H₃₂N₆O₄493.2 7.1 81 Ex. 53 247 1334 C₂₅H₂₈N₆O₄ 477.2 7.5 100 Ex. 53 248 1335C₂₃H₂₅N₅O₃ 420.2 5.6 99 Ex. 53 249 1337 C₂₂H₂₆N₆O₃ 423.2 7.1 100 Ex. 53250 1338 C₂₂H₂₆N₆O₂S 439.2 7.6 98 Ex. 53 251 1341 C₂₃H₂₈N₆O₂S 453.2 8.3100 Ex. 53 252 1364 C₂₁H₂₃N₅O₂ 378.3 4.3 98 Ex. 35 253 1374C₂₁H₂₁ClN₆O₂S 457.1 7.1 96 Ex. 35 254 1399 C₂₃H₂₅ClN₆O₂S 485.2 8.0 92Ex. 36 255 1405 C₂₄H₂₉N₅O₂ 420.2 6.1 100 Ex. 36 256 1413 C₂₅H₂₆ClN₅O₂S497.9 8.7 96 Ex. 36 257 1415 C₂₄H₂₇ClN₆O₂S 499.1 8.6 100 Ex. 36 258 1423C₂₅H₃₁N₅O₂ 434.4 6.5 98 Ex. 36 259 1427 C₂₅H₂₉ClN₆O₂S 513.2 9.3 96 Ex.36 260 1430 C₂₁H₂₁ClN₆O₂S 457.1 7.1 89 Ex. 35 261 1445 C₂₄H₂₇ClN₆O₂S499.2 8.8 100 Ex. 36 262 1482 C₂₅H₃₁N₅O₂ 434.4 6.8 96 Ex. 35 263 1486C₂₅H₂₉ClN₆O₂S 513.2 9.5 100 Ex. 36 264 1490 C₂₂H₂₇N₅O₂ 394.4 5.4 98 Ex.35 265 1494 C₂₂H₂₅ClN₆O₂S 473.2 8.2 98 Ex. 35 266 1511 C₂₆H₂₃ClN₆O₂S519.1 6.5 91 Ex. 33 267 1514 C₂₁H₁₉ClN₆O₂S 455.1 6.9 87 Ex. 35 268 1519C₂₀H₂₃N₅O₂S 398.2 4.9 100 Ex. 36 269 1520 C₂₁H₂₀ClN₅O₂S₂ 474.0 5.3 98Ex. 35 270 1522 C₂₄H₂₅ClN₆O₃S 513.1 4.2 100 Ex. 36 271 1530C₂₅H₂₇ClN₆O₂S 512.9 5.4 92 Ex. 36 272 1533 C₂₀H₁₄ClF₄N₅O₂S 500.0 6.3 65Ex. 35 273 1535 C₂₁H₁₃ClF₇N₅O₂S 568.0 7.7 96 Ex. 35 274 1549 C₂₅H₃₁N₅O₂434.2 6.8 100 Ex. 35 275 1553 C₂₅H₂₉ClN₆O₂S 513.2 9.5 90 Ex. 35 276 1554C₂₆H₃₃N₅O₂ 448.2 7.5 100 Ex. 35 277 1558 C₂₆H₃₁ClN₆O₂S 527.2 10.3 95 Ex.35 278 1566 C₂₄H₂₅ClN₆O₂S 497.2 8.3 97 Ex. 36 279 1589 C₂₃H₂₅F₂N₅O₂442.23 5.3 98 Ex. 36 280 1600 C₂₃H₂₃ClF₂N₆O₂S 521.2 7.8 98 Ex. 36 2811623 C₂₇H₃₅N₅O₂ 462.2 7.5 100 Ex. 35 7.7 282 1647 C₂₄H₂₆F₃N₅O₂ 474.2 6.279 Ex. 36 6.5 283 1654 C₂₄H₂₄ClF₃N₆O₂S 553.2 9.1 99 Ex. 36 284 1660C₂₅H₃₁N₅O₂ 434.3 6.5 99 Ex. 36 6.6 285 1661 C₂₅H₂₉ClN₆O₂S 513.2 9.3 98Ex. 36 9.4 286 1673 C₂₂H₂₅N₅O₃ 408.2 4.5 100 Ex. 36 287 1679C₂₂H₂₃ClN₆O₃S 487.1 6.4 95 Ex. 36 288 1682 C₂₈H₃₁ClN₆O₄S 583.2 6.9 96Ex. 36 289 1691 C₂₈H₃₁ClN₆O₄S 583.2 6.9 98 Ex. 36 290 1693 C₂₇H₃₂ClN₇O₄S586.2 8.4 95 Ex. 36 291 1695 C₂₇H₃₂ClN₇O₄S 586.2 8.6 95 Ex. 36 292 1696C₂₈H₃₁ClN₆O₄S 583.1 7.0 99 Ex. 36 293 1697 C₂₇H₃₂ClN₇O₄S 586.2 8.6 94Ex. 36 294 1698 C₂₆H₃₀ClN₇O₄S 572.1 7.8 93 Ex. 36 295 1699 C₂₇H₂₉ClN₆O₄S569.1 6.2 98 Ex. 36 296 1700 C₂₆H₃₀ClN₇O₄S 572.2 7.8 92 Ex. 36 297 1715C₂₉H₃₃ClN₆O₃S 581.2 6.3 93 Ex. 36 298 1719 C₂₇H₂₇ClN₆O₃S 551.1 5.2 96Ex. 36 299 1721 C₂₈H₂₉ClN₆O₃S 565.2 5.7 93 Ex. 36 300 1739 C₂₇H₃₁ClN₆O₂S539.2 4.7 90 Ex. 36 301 1748 C₂₈H₃₃ClN₆O₂S 553.2 5.1 95 Ex. 36 302 1751C₂₈H₃₃ClN₆O₂S 553.2 5.2 96 Ex. 36 303 1753 C₂₉H₃₅ClN₆O₂S 567.2 5.5 89Ex. 36 304 1758 C₂₇H₂₉ClN₆O₂S 537.1 4.7 96 Ex. 36 305 1778 C₂₅H₂₂F₃N₅O₂482.3 6.5 99 Ex. 36 306 1804 C₂₇H₂₁ClN₆O₂S 530.9 7.4 92 Ex. 36 307 1805C₂₈H₂₃ClN₆O₂S 543.1 8.1 89 Ex. 36 308 1806 C₂₇H₂₂ClN₅O₂S 516.1 6.8 96Ex. 35 309 1808 C₂₇H₂₂ClN₅O₂S 518.0 8.1 90 Ex. 36 310 1823 C₂₆H₂₃ClN₆O₂S519.1 5.2 94 Ex. 36 311 1828 C₂₇H₂₅ClN₆O₂S 533.1 5.2 89 Ex. 36 312 1833C₂₆H₂₁ClN₆O₂S 517.1 5.9 86 Ex. 36 313 1843 C₂₃H₂₅N₅O₃ 419.2 4.6 86 Ex.36 314 1846 C₂₆H₂₇N₅O₂ 441.2 6.1 90 Ex. 36 315 1849 C₂₈H₃₆N₆O₄ 520.3 6.339 Ex. 36 316 1852 C₂₉H₃₈N₆O₄ 534.3 6.9 43 Ex. 36 317 1855 C₁₉H₁₈F₃N₅O₂406.2 4.4 98 Ex. 36 318 1860 C₁₉H₁₆ClF₃N₆O₂S 485.1 7.4 91 Ex. 36 3191861 C₁₈H₁₆ClF₂N₅O₂ 408.2 4.9 36 Ex. 36 320 1865 C₂₀H₂₂ClN₅O₂ 400.3 4.660 Ex. 35 321 1868 C₂₁H₂₃N₅O₂ 378.3 4.4 97 Ex. 35 322 1885 C₂₀H₂₀F₃N₅O₂420.1 5.0 100 Ex. 36 323 1890 C₂₀H₁₈ClF₃N₆O₂S 499.1 7.7 98 Ex. 36 3241891 C₂₄H₂₉N₅O₂ 420.2 6.3 100 Ex. 36 325 1894 C₂₄H₂₇ClN₆O₂S 499.2 9.0100 Ex. 35 326 1899 C₂₁H₂₂F₃N₅O₂ 434.1 5.5 100 Ex. 36 327 1900C₂₁H₂₀ClF₃N₆O₂S 513.1 8.2 98 Ex. 36 328 1913 C₂₁H₂₀N₆O₂ 389.1 4.1 100Ex. 36 329 1915 C₂₁H₂₁Cl₂N₅O₂ 446.1 5.5 100 Ex. 36 330 2003 C₂₄H₂₇ClN₆O₂467.2 8.6 70 Ex. 53 331 2004 C₂₆H₂₅N₅O₂ 440.5 6.0 99 Ex. 35 332 2005C₂₂H₂₃ClN₆O₂S 471.0 7.2 97 Ex. 32 333 2006 C₂₃H₂₃ClN₆O₂S 483.0 7.4 97Ex. 32 334 2007 C₂₄H₂₁F₃N₆O₂ 483.3 7.0 99 Ex. 32 335 2008 C₂₄H₂₁F₃N₆O₃499.3 7.1 96 Ex. 32 336 2009 C₂₃H₁₇Cl₂N₇O₂S 526.0 6.5 90 Ex. 33 337 2010C₂₅H₂₀ClFN₆O₂S 523.1 6.3 97 Ex. 32 338 2011 C₂₄H₂₁ClFN₇O₂S 526.1 7.9 97Ex. 32 339 2012 C₂₄H₂₀ClN₇O₂S 506.1 4.0 81 Ex. 33 340 2013 C₂₅H₂₃F₃N₆O₃513.1 6.8 100 Ex. 32 341 2014 C₂₅H₂₇ClN₆O₂S 511.0 9.4 97 Ex. 32 342 2015C₂₄H₂₈ClN₇O₂S 514.1 8.5 100 Ex. 32 343 2016 C₂₅H₂₁ClN₆O₂S 505.0 7.7 93Ex. 32 344 2017 C₂₄H₂₁F₃N₆O₂ 483.2 6.8 100 Ex. 32 345 2018 C₂₄H₂₁F₃N₆O₂483.3 6.0 99 Ex. 32 346 2019 C₂₄H₂₆ClN₇O₃S 528.1 4.4 96 Ex. 33 347 2020C₂₅H₂₈ClN₇O₃S 542.1 4.3 100 Ex. 33 348 2021 C₂₅H₂₈ClN₇O₂S 526.1 4.8 98Ex. 33 349 2022 C₂₅H₃₂N₆O₂ 449.2 6.7 100 Ex. 32 350 2023 C₂₆H₂₉ClN₆O₂S525.1 7.3 98 Ex. 32 351 2024 C₂₅H₃₀ClN₇O₂S 528.1 8.8 98 Ex. 33 352 2025C₂₆H₂₉ClN₆O₂S 525.2 7.2 94 Ex. 33 353 2026 C₂₅H₃₀ClN₇O₂S 528.1 8.9 100Ex. 32 354 2027 C₂₅H₂₇ClN₆O₃S 527.2 5.5 96 Ex. 33 355 2028 C₂₈H₂₉ClN₆O₂S549.0 9.7 97 Ex. 32 356 2029 C₂₅H₂₀ClFN₆O₂S 523.1 5.8 97 Ex. 32 357 2031C₂₄H₂₃FN₆O₂ 447.1 5.5 100 Ex. 32 358 2032 C₂₅H₂₀ClFN₆O₂S 523.1 6.3 98Ex. 32 359 2033 C₂₄H₂₁ClFN₇O₂S 526.1 7.8 94 Ex. 32 360 2034C₂₅H₁₉ClF₂N₆O₂S 541.0 6.7 96 Ex. 32 361 2036 C₂₄H₂₀ClF₂N₇O₂S 544.1 7.694 Ex. 32 362 2040 C₂₄H₂₂Cl₂N₆O₂ 497.3 6.6 100 Ex. 33 363 2042C₂₅H₂₃F₃N₆O₂ 497.3 6.3 97 Ex. 33 364 2046 C₂₅H₂₃F₃N₆O₂ 497.3 6.6 98 Ex.33 365 2049 C₂₅H₂₁ClF₃N₇O₂S 576.1 8.9 100 Ex. 32 366 2052C₂₆H₂₀ClF₃N₆O₃S 589.0 7.6 98 Ex. 32 367 2053 C₂₅H₂₁ClF₃N₇O₃S 592.1 9.0100 Ex. 32 368 2054 C₂₄H₂₄F₃N₇O₃ 516.2 8.0 100 Ex. 32 369 2056C₂₆H₂₀ClF₃N₆O₃S 589.0 7.7 98 Ex. 32 370 2058 C₂₅H₂₁ClF₃N₇O₃S 592.1 9.1100 Ex. 32 371 2060 C₂₆H₂₃ClN₆O₃S 535.1 6.3 99 Ex. 32 372 2062C₂₆H₂₃ClN₆O₃S 535.1 6.2 96 Ex. 32 373 2063 C₂₅H₂₄ClN₇O₃S 538.1 7.7 91Ex. 32 374 2064 C₂₅H₂₆N₆O₃ 459.1 5.3 100 Ex. 32 375 2065 C₂₆H₂₃ClN₆O₃S535.1 6.1 99 Ex. 32 376 2067 C₂₅H₂₄ClN₇O₃S 538.1 7.7 91 Ex. 32 377 2068C₂₇H₂₅ClN₆O₄S 565.1 5.8 89 Ex. 32 378 2069 C₂₆H₂₆ClN₇O₄S 568.1 7.0 63Ex. 32 379 2070 C₂₇H₂₅ClN₆O₄S 565.1 6.5 87 Ex. 32 380 2071 C₂₆H₂₆ClN₇O₄S568.1 7.7 94 Ex. 32 381 2072 C₂₆H₂₁ClN₆O₄S 549.1 6.2 96 Ex. 32 382 2073C₂₅H₂₂ClN₇O₄S 552.0 7.5 90 Ex. 32 383 2078 C₂₆H₂₃ClN₆O₄S₂ 583.0 5.6 78Ex. 32 384 2080 C₂₆H₂₇ClN₈O₂S 551.0 5.8 95 Ex. 33 385 2081 C₂₄H₂₀ClN₇O₂S506.1 4.1 65 Ex. 33 386 2083 C₂₄H₂₀ClN₇O₂S 506.1 4.1 75 Ex. 32 387 2085C₂₄H₁₉Cl₂N₇O₂S 540.0 5.0 88 Ex. 32 388 2086 C₂₃H₂₀Cl₂N₈O₂S 543.0 6.9 100Ex. 33 389 2087 C₂₃H₁₉ClN₆O₃S 495.6 5.6 90 Ex. 32 390 2089C₂₃H₁₉ClN₆O₂S₂ 511.0 5.8 94 Ex. 32 391 2093 C₂₆H₂₃ClN₆O₂S 519.1 6.5 98Ex. 32 392 2094 C₂₆H₂₃ClN₆O₂S 519.1 6.5 98 Ex. 32 393 2095 C₂₇H₂₅ClN₆O₃S549.1 6.4 100 Ex. 32 394 2096 C₂₇H₂₅ClN₆O₃S 549.1 6.4 94 Ex. 32 395 2097C₂₆H₂₆ClN₇O₃S 552.1 7.9 94 Ex. 32 396 2098 C₂₅H₂₃ClFN₇O₂S 540.1 8.2 100Ex. 32 397 2099 C₂₅H₁₈ClF₃N₆O₂S 558.9 9.6 96 Ex. 32 398 2100C₂₃H₁₇Cl₂N₇O₂S 526.0 6.0 93 Ex. 33 399 2101 C₂₁H₁₆ClN₇O₂S₂ 497.9 6.4 85Ex. 32 400 2102 C₂₄H₂₀ClF₂N₇O₂S 544.1 8.1 93 Ex. 33 401 2103C₂₅H₂₂F₄N₆O₂ 515.3 6.7 97 Ex. 33 402 2105 C₂₅H₂₂F₄N₆O₂ 515.3 6.6 100 Ex.33 403 2107 C₃₀H₂₈N₆O₂ 505.4 7.0 80 Ex. 33 404 2109 C₂₅H₂₁ClN₆O₂S 505.16.1 89 Ex. 33 405 2110 C₁₈H₂₁N₅O₃ 356.3 4.5 91 Ex. 28 406 2116C₂₀H₂₆N₆O₃ 399.1 6.7 100 Ex. 28 407 2119 C₂₃H₃₂N₆O₃ 441.2 8.1 86 Ex. 28408 2120 C₁₉H₂₂N₄O₄ 371.0 7.4 33 Ex. 70 409 2122 C₂₃H₂₆N₆O₄ 451.0 7.7 41Ex. 70 410 2127 C₁₈H₁₉ClN₈O₃S 462.9 8.6 98 Ex. 28 411 2141 C₂₆H₂₈N₄O₄461.0 11.5 99 Ex. 10 412 2142 C₃₁H₃₁N₅O₄ 538.0 9.3 99 Ex. 28 413 2143C₃₀H₃₂N₆O₄ 541.1 11.4 70 Ex. 28 414 2146 C₂₂H₂₂ClN₅O₃S 472.1 6.8 99 Ex.35 415 2147 C₂₅H₂₀ClN₅O₃S 506.1 7.1 98 Ex. 35 416 2148 C₂₂H₂₂ClN₅O₃S472.1 6.8 99 Ex. 35 417 2158 C₂₀H₂₃N₅O₂ 366.4 4.7 100 Ex. 49 418 2161C₂₄H₂₉N₅O₂ 420.3 7.1 93 Ex. 63 419 2162 C₂₃H₃₀N₆O₂ 423.3 7.8 100 Ex. 63420 2164 C₂₄H₂₈N₆O₂S 465.3 8.6 100 Ex. 53 421 2165 C₂₉H₃₃N₅O₄ 516.4 7.599 Ex. 53 422 2165 C₂₅H₂₇N₅O₃ 446.2 7.3 98.9 Ex. 53 423 2166 C₂₈H₃₄N₆O₄519.3 8.1 100 Ex. 53 424 2170 C₂₄H₂₈N₆O₃ 449.3 8.3 100 Ex. 53 425 2175C₃₀H₃₁N₅O₃ 510.3 7.6 88 Ex. 63 426 2176 C₂₉H₃₂N₆O₃ 513.4 8.2 100 Ex. 63427 2183 C₂₄H₂₄FN₅O₂S 466.3 6.2 98 Ex. 53 428 2184 C₂₃H₂₅FN₆O₂S 469.37.6 100 Ex. 53 429 2185 C₂₈H₃₀FN₅O₄ 520.3 6.1 99 Ex. 53 430 2186C₂₇H₃₁FN₆O₄ 523.3 7.7 98 Ex. 53 431 2187 C₂₄H₂₄FN₅O₃ 450.3 5.9 98 Ex. 53432 2188 C₂₃H₂₅FN₆O₃ 453.3 7.3 100 Ex. 53 433 2202 C₂₁H₂₅N₅O₂ 380.4 5.3100 Ex. 49 434 2209 C₂₁H₁₉N₅O₂ 374.3 5.1 100 Ex. 49 435 2210 C₂₄H₂₂FN₅O₂432.2 7.0 93 Ex. 63 436 2211 C₂₃H₂₃FN₆O₂ 435.3 7.8 100 Ex. 63 437 2212C₂₅H₂₂F₃N₅O₂ 482.3 7.2 79 Ex. 63 438 2224 C₂₅H₂₂F₃N₅O₃ 498.3 7.5 99 Ex.63 439 2240 C₂₅H₂₄FN₅O₂ 446.3 7.0 96 Ex. 63 440 2241 C₂₄H₂₅FN₆O₂ 449.37.6 100 Ex. 63 441 2265 C₂₅H₃₁N₅O₂ 434.3 7.5 98 Ex. 63 442 2266C₂₄H₃₂N₆O₂ 437.4 8.3 100 Ex. 63 443 2267 C₂₆H₂₉N₅O₂S 476.3 7.5 98 Ex. 53444 2268 C₂₅H₃₀N₆O₂S 479.3 9.1 100 Ex. 53 445 2270 C₂₉H₃₁N₅O₄ 514.0 8.2100 Ex. 53 446 2271 C₂₆H₂₉N₅O₃ 460.3 7.4 93 Ex. 53 447 2272 C₂₅H₃₀N₆O₃463.3 8.8 100 Ex. 53 448 2275 C₂₆H₃₃N₅O₂ 448.3 8.2 83 Ex. 63 449 2277C₂₅H₃₄N₆O₂ 451.4 9.0 100 Ex. 63 450 2281 C₂₇H₃₁N₅O₂S 490.4 7.7 100 Ex.53 451 2282 C₂₆H₃₂N₆O₂S 493.3 9.8 100 Ex. 53 452 2287 C₃₁H₃₇N₅O₄ 544.57.7 100 Ex. 53 453 2288 C₂₉H₃₆N₆O₄ 533.3 9.0 100 Ex. 53 454 2288C₃₀H₃₈N₆O₄ 547.4 9.4 99 Ex. 53 455 2290 C₂₇H₃₁N₅O₃ 474.5 7.5 100 Ex. 53456 2291 C₂₆H₃₂N₆O₃ 477.4 9.5 100 Ex. 53 457 2296 C₂₅H₂₅N₅O₂ 428.3 5.996 Ex. 63 458 2298 C₂₄H₂₂FN₅O₂ 432.3 5.8 95 Ex. 63 459 2299 C₁₉H₂₃N₅O₂354.4 4.6 100 Ex. 49 460 2300 C₁₈H₁₉N₅O₄ 370.3 2.2 100 Ex. 49 461 2301C₁₈H₂₁N₅O₃ 356.4 2.5 100 Ex. 49 462 2305 C₂₅H₂₄FN₅O₂ 446.3 5.9 98 Ex. 63463 2311 C₂₆H₂₄F₃N₅O₂ 496.3 7.1 98 Ex. 63 464 2325 C₂₆H₂₄F₃N₅O₃ 512.37.3 98 Ex. 63 465 2329 C₂₆H₂₇N₅O₂ 442.4 6.3 98 Ex. 63 466 2336C₂₇H₂₅N₅O₂S 484.3 7.3 98 Ex. 53 467 2337 C₂₆H₂₆N₆O₂S 487.3 8.7 100 Ex.53 468 2340 C₂₄H₂₆N₆O₂ 431.4 7.4 100 Ex. 53 469 2341 C₂₆H₂₇N₅O₂ 442.56.4 100 Ex. 53 6.6 470 2342 C₃₁H₂₉N₅O₂ 504.4 7.7 100 Ex. 53 7.9 471 2343C₃₂H₂₉N₅O₃ 532.4 8.0 100 Ex. 53 472 2344 C₃₁H₃₁N₅O₄ 538.5 6.9 100 Ex. 53473 2347 C₂₇H₂₅N₅O₃ 468.3 7.1 98 Ex. 53 474 2348 C₂₆H₂₆N₆O₃ 471.3 8.4100 Ex. 53 475 2350 C₂₃H₂₃N₅O₃ 418.3 5.1 98 Ex. 63 476 2356 C₂₆H₂₇N₅O₂442.2 7.1 87 Ex. 63 477 2357 C₂₅H₂₈N₆O₂ 445.3 7.8 100 Ex. 63 478 2446C₁₇H₁₁ClN₄O 323.2 4.5 100 Ex. 53 479 2448 C₁₇H₁₂N₄O₂ 305.3 2.5 100 Ex.53 480 2452 C₁₈H₁₄N₄O₂ 319.3 4.2 100 Ex. 53 481 2459 C₁₈H₁₄N₄O₂ 319.32.9 100 Ex. 53 482 2469 C₁₆H₁₃N₅O 292.2 2.9 100 Ex. 53 483 2471C₁₅H₁₀N₄OS 295.3 3.2 100 Ex. 53 484 2481 C₁₅H₁₀N₄O₂ 279.3 2.5 100 Ex. 53485 2484 C₁₇H₁₀Cl₂N₄O 357.0 5.5 100 Ex. 53 486 2486 C₁₉H₁₆N₄O₃ 349.2 4.1100 Ex. 53 487 2490 C₁₈H₁₅N₅O₃S 382.3 4.0 100 Ex. 53 488 2492 C₁₈H₁₂N₄O₃333.3 2.7 100 Ex. 53 489 2495 C₁₉H₁₃N₅O 328.3 5.1 100 Ex. 53 490 2500C₂₆H₂₂N₄O₃ 439.0 7.5 94 Ex. 53 491 1562 C₂₄H₂₇N₅O₂ 418.5 5.7 99 Ex. 36492 1895 C₂₅H₂₈N₆O₂ 445.5 5.7 99 Ex. 36 493 1875 C₂₁H₁₉F₆N₅O₂ 488.3 6.599 Ex. 36 494 2514 C₃₀H₃₁N₅O₃ 510.5 6.6 99 Ex. 36

Example 495

¹H-NMR (400 MHz, DMSO-d₆ or CDCl₃) of the compounds according to thepresent invention were measured. Data of chemical shift values (δ: ppm)and coupling constant (J: Hz) are shown in Table 3. Compound numbers inTable 3 designate compounds in Table 1 listed as preferred specificexamples, and example numbers in the table denote examples ofcorresponding synthesized compounds

Ex. Compound no. no. NMR data δ(ppm) Solvent 72 27 1.28-1.44(m, 2H),1.76(m, 2H), 2.76(m, 1H), DMSO-d6 2.84-3.01(m, 2H), 3.15(m, 1H), 3.68(m,1H), 3.87(d, J=12.96, 1H), 4.39(d, J=11.96, 1H), 4.62(m, 2H), 7.52(m,2H), 7.63(m, 1H), 7.79(dd, J=5.38, J=8.06, 1H), 7.97(m, 3H), 8.24(s,1H), 8.59(d, J=5.36, 1H), 8.78(d, J=8.32, 1H), 9.37(s, 1H), 12.24(brs,1H). 73 29 0.00(m, 2H), 0.25(m, 2H), 2.28(m, 1H), 2.37(t, J=6.70,DMSO-d6 2H), 4.34(t, J=6.60, 2H), 7.58(dd, J=5.50, J=7.94, 1H), 7.69(d,J=3.92, 1H), 7.73(s, 1H), 7.86(s, 1H), 8.35(d, J=5.36, 1H), 8.58(d,J=8.28, 1H), 9.14(s, 1H), 12.02(brs, 1H). 75 80 3.96(m, 2H), 4.49(m,1H), 4.88(m, 1H), 7.11(m, DMSO-d6 1H), 7.73-7.79(m, 2H), 7.83(m, 1H),7.88(brs, 1H), 8.03(t, J=7.7, 1H), 8.18(d, J=8.5, 1H), 8.64(s, 1H),10.00(brs, 1H), 12.29(brs, 1H). 202 1106 1.44(brs, 2H), 1.62(brs, 4H),3.45(m, 4H), DMSO-d6 5.39(s, 2H), 7.81(dd, J=5.48, J=8.16, 1H), 7.98(s,1H), 8.09(s, 1H), 8.60(d, J=5.40, 1H), 8.80(d, J=8.04, 1H), 9.39(s, 1H),12.18(brs, 1H). 206 1161 5.36(s, 2H), 7.05(m, 1H), 7.31(t, J=7.56, 2H),DMSO-d6 7.58(d, J=7.56, 2H), 7.81(dd, J=5.24, J=8.16, 1H), 8.00(s, 1H),8.18(s, 1H), 8.61(d, J=5.36, 1H), 8.80(d, J=8.04, 1H), 9.41(s, 1H),10.37(s, 1H), 12.26(brs, 1H). 208 1170 1.19-1.23(m, 3H), 4.13-4.20(m,2H), 5.30(s, 2H), DMSO-d6 7.79(m, 1H), 8.00(d, J=3.92, 1H), 8.15(d,J=4.16, 1H), 8.60(m, 1H), 8.76(d, J=8.07, 1H), 9.37(s, 1H), 12.28(brs,1H). 209 1174 4.06(s, 3H), 7.84(dd, J=5.36, J=8.03, 1H), DMSO-d6 7.96(s,1H), 8.16(s, 1H), 8.61(d, J=5.12, 1H), 8.84(d, J=7.75, 1H), 9.39(s, 1H),12.21(brs, 1H). 212 1179 5.67(s, 2H), 7.13-7.36(m, 5H), 7.80(dd, J=5.35,DMSO-d6 J=8.03, 1H), 8.00(s, 1H), 8.36(s, 1H), 8.60(d, J=5.36, 1H),8.83(d, J=8.07, 1H), 9.40(s, 1H), 12.29(brs, 1H).

Example 496 Determination of Inhibition of GSK-3 Activity

The reaction was initiated by adding 25 μL of phospho-glycogen synthasepeptide-2 substrate solution [containing 6 μM phospho-glycogen synthasepeptide-2, 20 μM ATP, 16 mM MOPS buffer (pH 7.0), 0.2 mM EDTA, 20 mMmagnesium acetate, 0.1 μ Ci[γ-³³P]ATP (relative activity: approximately110 TBq/mmol)] to 5 μL of each test compound using 5% dimethylsulfoxideas a solvent, and further adding 20 μL of GSK-3β enzyme solution[containing 10 mU recombinant human GSK-3β, 20 mM MOPS buffer (pH 7.0),1 mM EDTA, 0.1% polyoxyethylene lauryl ether(23 Lauryl Ether; Brij 35),5% glycerol, and 0.1% β-mercaptoethanol. After 20 minutes at roomtemperature, the reaction was terminated by the addition of theequivalent amount of 200 mM phosphoric acid solution. 90 μL of thereaction product was spotted onto a multiscreen PH plate (manufacturedby Millipore) and washed with 100 mM phosphoric acid solution. The platewas dried, and 30 μL of MicroScint-O (manufactured by PackardBioScience) was added thereto. To evaluate inhibitory activity, cpm wascounted using a scintillation counter. Here, Phospho GS Peptide 2 is anamino acid peptide having the following sequence:Tyr-Arg-Arg-Ala-Ala-Val-Pro-Pro-Ser-Pro-Ser-Leu-Ser-Arg-His-Ser-Ser-Pro-His-Gln-Ser(P)-Glu-Asp-Glu-Glu-Glu.

GSK-3 inhibitor activity values (IC₅₀ values) of the compounds accordingto the present invention were measured by the method described above. Asa result, an inhibition activity of IC₅₀<100 nM was confirmed incompounds of compound numbers 263, 280, 287, 297, 615, 617, 618, 627,629, 641, 668, 760, 785, 1014, 1183, 1206, 1216, 1217, 1228, 1237, 1243,1250, 1257, 1271, 1286, 1287, 1288, 1293, 1296, 1374, 1399, 1405, 1415,1423, 1427, 1430, 1445, 1494, 1514, 1549, 1553, 1566, 1589, 1600, 1647,1654, 1660, 1661, 1679, 1693, 1695, 1715, 1721, 1890, 1900, 2007, 2008,2010, 2011, 2012, 2013, 2014, 2015, 2017, 2022, 2026, 2031, 2032, 2033,2034, 2036, 2040, 2042, 2046, 2049, 2053, 2054, 2058, 2062, 2063, 2064,2065, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2078, 2080, 2083, 2085,2086, 2095, 2097, 2098, 2102, 2103, 2105, 2107, 2212, 2224, 2311.

Also, an inhibition activity of 20 nM<IC₅₀<100 nM was confirmed incompounds of compound numbers 40, 217, 219, 230, 245, 269, 288, 303,595, 596, 601, 602, 616, 626, 628, 634, 646, 657, 659, 664, 667, 668,673, 689, 694, 696, 723, 733, 734, 741, 768, 770, 776, 793, 795, 801,802, 803, 804, 805, 806, 807, 809, 810, 812, 915, 1182, 1186, 1236,1260, 1277, 1278, 1282, 1284, 1335, 1337, 1338, 1341, 1364, 1413, 1482,1486, 1490, 1519, 1520, 1533, 1554, 1558, 1623, 1673, 1682, 1691, 1696,1700, 1719, 1739, 1748, 1751, 1753, 1758, 1778, 1806, 1808, 1846, 1849,1852, 1855, 1865, 1868, 1885, 1894, 1899, 2004, 2005, 2006, 2016, 2018,2019, 2020, 2021, 2024, 2025, 2027, 2029, 2052, 2056, 2060, 2081, 2087,2089, 2094, 2099, 2100, 2101, 2146, 2147, 2148, 2161, 2175, 2183, 2184,2210, 2211, 2240, 2241, 2265, 2266, 2275, 2296, 2298, 2305, 2325, 2329,2331, 2332, 2336, 2337, 2341, 2342, 2347, 2348, 2350, 2448, 2486, 2492.

Also, an inhibition activity of 100 nM<IC₅₀<1 μM was confirmed incompounds of compound numbers 81, 84, 254, 257, 320, 321, 330, 348, 361,492, 504, 536, 550, 605, 678, 684, 702, 704, 709, 713, 718, 724, 729,808, 811, 917, 918, 946, 1001, 1002, 1007, 1008, 1178, 1181, 1184, 1185,1258, 1259, 1261, 1262, 1297, 1331, 1333, 1334, 1511, 1522, 1530, 1535,1697, 1804, 1805, 1823, 1833, 1843, 1860, 1861, 1891, 1913, 1915, 2003,2023, 2028, 2093, 2096, 2109, 2116, 2158, 2162, 2164, 2165, 2166, 2170,2176, 2186, 2187, 2188, 2202, 2209, 2264, 2267, 2268, 2269, 2270, 2271,2272, 2277, 2281, 2282, 2288, 2290, 2291, 2292, 2299, 2300, 2340, 2344,2345, 2356, 2357, 2445, 2446, 2452, 2459, 2469, 2471, 2481, 2484, 2490,2495.

Compound numbers designate compounds in Table 1 listed as preferredspecific examples.

As described above, the pyrrolopyrimidine derivatives according to thepresent invention exhibit strong inhibitory activity against GSK-3.Therefore, the pyrrolopyrimidine derivatives according to the presentinvention have been found to be inhibitors of GSK-3 activity to be usedin prevention and/or treatment of various diseases associated withGSK-3, which are clinically applicable compounds.

Example 493 Preparation of Tablets

Tablets each comprising the following ingredients were prepared.

Compound (Example 1) 50 mg Lactose 230 mg  Potato starch 80 mgPolyvinylpyrrolidone 11 mg Magnesium stearate  5 mg

The compound of the present invention (the compound prepared in Example1), lactose, and potato starch were mixed, homogenously wetted with 20%ethanol solution of polyvinylpyrrolidone, passed through a 20 meshsieve, dried at 45° C., and passed through again a 15 mesh sieve toobtain granules. The thus obtained granules were mixed with magnesiumstearate and compressed into tablets.

Reference Example 15 Synthesis ofN-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}-2,2,2-trifluoroacetoamide

A phosphorus oxychloride (3.0 mL) solution ofN-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide(333 mg) was stirred at 110° C. for 2 hours. The reaction mixture wascooled to room temperature, and excess phosphorus oxychloride wasdistilled off under reduced pressure. A residue was dried in vacuo toobtain a crude product of the title compound as a brown oily compound.The product was not purified, but used for the following reaction. TheESI/MS data of the compound is given below.

ESI/MS m/e: 535.2 (M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 16 Synthesis ofN-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by usingN-{2-[7-promo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide(333 mg) in a similar manner to that in Reference Example 15. The ESI/MSdata of the compound is given below.

ESI/MS m/e: 489.0 (M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 17 Synthesis ofN-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by usingN-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide(333 mg) in a similar manner to that in Reference Example 15. The ESI/MSdata of the compound is given below.

ESI/MS m/e: 443.4 (M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

INDUSTRIAL APPLICABILITY

The pyrrolopyrimidinone derivatives of Formula (I) according to thepresent invention and its pharmaceutically acceptable salts have GSK-3inhibitory activity and are used as effective ingredients ofpharmaceutical products. Therefore, pharmaceutical agents containingthese compounds as effective ingredients are expected as promisingtherapeutic drugs or preventive drugs in GSK-3 mediated diseasesincluding diabetes, diabetic complications, Alzheimer's disease,neurodegenerative diseases manic depression, traumatic cerebrospinalinjury, alopecia, inflammatory diseases, cancer and immunodeficiency.

1. A compound represented by the formula (I) or its pharmaceuticallyacceptable salts:

wherein A¹ is —(CH₂)₂— or —(CH₂)₃— A² represents a group that links A¹with G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)-O-G¹, A¹-C(═O)—NR¹⁰¹-G¹,A¹-C(═S)—NR¹⁰²-G¹, A¹-C(═NR¹⁰³)-G¹,A¹-O-G¹, A¹-O-C(═O)-G¹, A¹-NR¹⁰⁴-G¹,A¹-NR¹⁰⁵-C(═O)-G¹, A¹-NR¹⁰⁶—S(═O)₂-G¹, A¹-NR¹⁰⁷—C(═O)O-G¹,A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹—NR¹¹⁰-C(═S)-G¹, A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹,A¹-S-G¹, A¹-S(═O)-G¹, A¹-S(═O)₂—NR¹¹³-G¹, A¹-CR¹¹⁴═CH-G¹,A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹, or A¹-CF═CR¹¹⁷-G¹; G¹ represents asingle bond or represents a divalent group which is obtainable byremoving two hydrogen atoms from any one of an optionally substitutedalicyclic hydrocarbon having 3 to 8 carbon atoms, an optionallysubstituted aromatic hydrocarbon having 6 to 14 carbon atoms, and anoptionally substituted heterocyclic compound having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring, A³ represents a single bond orrepresents an optionally substituted divalent acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms that links G¹ with A⁴ onthe same or different carbon atom; A⁴ represents a single bond orrepresents a group that links A³ with G² in the form of A³-C(═O)—O-G²,A³-C(═O)—NR¹²¹-G², A³-C(═S)—NR¹²²-G², A³-C(═NR¹²³)-G², A³-O-G²,A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G²,A³-NR¹²⁷—C(═O)—O-G², A³-NR¹²⁸—C(═O)—NR¹²⁹-G², A³-NR¹³⁰—C(═S)-G²,A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O_)-G², A³-S(═O)₂-G²,A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G²; G² is a hydrogen atom, anoptionally substituted acyclic aliphatic hydrocarbon group having 1 to10 carbon atoms, an optionally substituted alicyclic hydrocarbon grouphaving 3 to 10 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, or an optionallysubstituted heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring; A⁵ represents a single bond or —NR²⁰¹—; R² is a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an optionally substituted acyclic aliphatic hydrocarbon group having 1to 10 carbon atoms, an optionally substituted alicyclic hydrocarbongroup having 3 to 8 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, or an optionallysubstituted heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring; A⁶ represents a single bond-; R³ is an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, oran optionally substituted heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring; and R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹²¹,R¹²², R¹²³, R¹²⁴, R¹²⁵, R¹²⁶, R¹²⁷, R¹²⁸, R¹²⁹, R¹³⁰, R¹³¹, R¹³², R¹³³,and R²⁰¹ are each independently a hydrogen atom or an aliphatichydrocarbon group having 1 to 4 carbon atoms.
 2. The compound or apharmaceutically acceptable salt thereof according to claim 1, whereinA² represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—,—NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—.3. The compound or a pharmaceutically acceptable salt thereof accordingto claim 1, wherein A² represents —C(═O)—NH—, —NH—, —NH—C(═O)—,—NH—C(═O)—O—, or —NH—C(═O)—NH—.
 4. The compound or a pharmaceuticallyacceptable salt thereof according to claim 2, wherein combination of G¹,A³, A⁴, and G² is any of the combinations of 1 to 10 in the followingtable: Combination G¹ A³ A⁴ G² 1 group other single bond single bondhydrogen atom than single bond 2 single bond group other single bondhydrogen atom than single bond 3 group other single bond single bondgroup other than single than hydrogen bond atom 4 single bond groupother single bond group other than single than hydrogen bond atom 5group other single bond group other group other than single than singlethan hydrogen bond bond atom 6 single bond group other group other groupother than single than single than hydrogen bond bond atom 7 group othergroup other single bond group other than single than single thanhydrogen bond bond atom 8 group other group other group other groupother than single than single than single than hydrogen bond bond bondatom 9 group other group other group other hydrogen atom than singlethan single than single bond bond bond 10 single bond single bond singlebond hydrogen atom.


5. The compound or a pharmaceutically acceptable salt thereof accordingto claim 2, wherein G¹ represents a group other than a single bond, A³and A⁴ represent a single bond, and G² represents a hydrogen atom. 6.The compound or a pharmaceutically acceptable salt thereof according toclaim 2, wherein G¹ and A⁴ represent a single bond, A³ represents agroup other than a single bond, and G² represents a hydrogen atom. 7.The compound or a pharmaceutically acceptable salt thereof according toclaim 2, wherein G¹ represents a group other than a single bond, A³ andA⁴ represent a single bond, and G² represents a group other than ahydrogen atom.
 8. The compound or a pharmaceutically acceptable saltthereof according claim 2, wherein G¹ and A⁴ represent a single bond, A³represents a group other than a single bond, and G² represents a groupother than a hydrogen atom.
 9. The compound or a pharmaceuticallyacceptable salt thereof according to claim 8, wherein A³ represent analkylene group having 1 to 3 carbon atoms.
 10. The compound or apharmaceutically acceptable salt thereof according to claim 2, whereinG¹ and A⁴ represent a group other than a single bond, A³ represents asingle bond, and G² represents a group other than a hydrogen atom. 11.The compound or a pharmaceutically acceptable salt thereof according toclaim 10, wherein A² represents —C(═O)—, —C(═O)—NH—, or —NH—C(═O)—. 12.The compound or a pharmaceutically acceptable salt thereof according toclaim 2, wherein G¹ represents a single bond, A³ and A⁴ represent agroup other than a single bond, and G² represents a group other than ahydrogen atom.
 13. The compound or a pharmaceutically acceptable saltthereof according to claim 2, wherein G¹ and A³ represent a group otherthan a single bond, A⁴ represents a single bond, and G² represents agroup other than a hydrogen atom.
 14. The compound or a pharmaceuticallyacceptable salt thereof according to claim 13, wherein A³ represent analkylene group having 1 to 3 carbon atoms.
 15. The compound or apharmaceutically acceptable salt thereof according to claim 2, whereinG¹, A³ and A⁴ represent a group other than a single bond, and G²represents a group other than a hydrogen atom.
 16. The compound or apharmaceutically acceptable salt thereof according to claim 1, whereinA⁴ represents —O—.
 17. The compound or a pharmaceutically acceptablesalt thereof according to claim 2, wherein G¹, A³ and A⁴ represent agroup other than a single bond, and G² represents a hydrogen atom. 18.The compound or a pharmaceutically acceptable salt thereof according toclaim 2, wherein G¹, A³ and A⁴ represent a single bond, and G²represents a hydrogen atom.
 19. The compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein A¹ is —(CH₂)₂— or—(CH₂)₃—, A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents asingle bond, and A³ represents a divalent acyclic aliphatic hydrocarbongroup having 1 to 6 carbon atoms.
 20. The compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein A¹ is —(CH₂)₂— or—(CH₂)₃—, A² represents —NH—(C═O)—, —NH—(C═O)—NH—, and G¹ represents agroup other than a single bond.
 21. The compound or a pharmaceuticallyacceptable salt thereof according to claim 2, wherein G¹ represents anoptionally substituted aromatic hydrocarbon group, an optionallysubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, oran optionally substituted heterocyclic group, with the proviso that whenthe aromatic hydrocarbon group of G¹ is a phenyl group, or theheterocyclic group of G¹ is 5 or 6 membered monocyclic ring, then thephenyl group or the 5 or 6 membered monocyclic heterocyclic group of G¹is substituted, or the A³-G² portion represents those other than ahydrogen atom.
 22. The compound or a pharmaceutically acceptable saltthereof according to claim 2, wherein G¹ and A⁴ represent a single bond,A³ represents an optionally substituted acyclic aliphatic hydrocarbongroup having 1 to 6 carbon atoms, G² represents an optionallysubstituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, anoptionally substituted aromatic hydrocarbon group, or an optionallysubstituted heterocyclic group.
 23. The compound or a pharmaceuticallyacceptable salt thereof according to claim 2, wherein G¹ represents asingle bond, A³ represents an optionally substituted acyclic aliphatichydrocarbon group having 1 to 6 carbon atoms, and A⁴ represents —C(═O)—,—C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(O)—, —NR¹²⁵—C(═O)—,—NR¹²⁶—S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—,—NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³—, or—S(═O)₂—O—.
 24. The compound or a pharmaceutically acceptable saltthereof according to claim 1, wherein A⁵ represents a single bond. 25.The compound or a pharmaceutically acceptable salt thereof according toclaim 24, wherein R² represents an optionally substituted acyclicaliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionallysubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, anoptionally substituted aromatic hydrocarbon group having 6 to 14 carbonatoms, or an optionally substituted heterocyclic group.
 26. The compoundor a pharmaceutically acceptable salt thereof according to claim 24,wherein R² represents an acyclic aliphatic hydrocarbon group having 1 to10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbonatoms, an optionally substituted phenyl group, or an optionallysubstituted heterocyclic group having 1 or 2 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom, or a sulfur atom,in the ring.
 27. The compound or a pharmaceutically acceptable saltthereof according to claim 24, wherein R² represents a cyclopropylgroup, cyclobutyl group, cyclopropylmethyl group, methyl group, ethylgroup, vinyl group, isopropyl group, or 2-methyl-1-propenyl group. 28.The compound or a pharmaceutically acceptable salt thereof according toclaim 24, wherein R² represents a thienyl group, a pyridyl group, afuryl group, a pyrrolyl group, a pyrazolyl group, or phenyl group; anyof which may be further substituted by one or more of an alkyl grouphaving 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms,an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxylgroup, an alkoxycarbonyl group having 2 to 7 carbon atoms, a fluorineatom, or a chlorine atom.
 29. The compound or a pharmaceuticallyacceptable salt thereof according to claim 1 wherein R³ represents athienyl group, a pyridyl group, a furyl group, a pyrrolyl group, apyrazolyl group, or phenyl group; any of which may be furthersubstituted by one or more of an alkyl group having 1 to 4 carbon atoms.30. The compound or a pharmaceutically acceptable salt thereof accordingto any one of claims 1, 2-3 and 4-5, 7, 10-11, 16, 18, 20, and 24-28,wherein A³ represents a single bond and R³ represents a pyridyl group ora 1-oxypyridyl group, either of which may be further substituted by onealkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolylgroup; or N-methylpyrazolyl group.
 31. The compound or apharmaceutically acceptable salt thereof according to claim 27, whereinR³ represents a pyridyl group or a 1-oxypyridyl group, either of whichmay be further substituted by one alkyl group having 1 to 4 carbon atomsor one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group. 32.The compound or a pharmaceutically acceptable salt thereof according toclaim 28, R³ represents a pyridyl group or a 1-oxypyridyl group, eitherof which may be further substituted by one alkyl group having 1 to 4carbon atoms or one halogen atom; a pyrazolyl group; orN-methylpyrazolyl group.
 33. The compound or a pharmaceuticallyacceptable salt thereof according to any one of claims 19-20 and 21-23,wherein both of A⁵ represents a single bond.
 34. The compound or apharmaceutically acceptable salt thereof according to claim 33, whereinR² represents an optionally substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms, an optionally substituted alicyclichydrocarbon group having 3 to 8 carbon atoms, an optionally substitutedaromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionallysubstituted heterocyclic group, and R³ represents an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms or anoptionally substituted heterocyclic group.
 35. The compound or apharmaceutically acceptable salt thereof according to claim 33, whereinR² represents an optionally substituted acyclic aliphatic hydrocarbongroup having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having3 to 8 carbon atoms, an optionally substituted phenyl group, or anoptionally substituted heterocyclic group having 1 or 2 atoms selectedfrom the group consisting of an oxygen atom, a nitrogen atom, and asulfur atom, in the ring, and R³ represents a thienyl group, a pyridylgroup, a furyl group, a pyrrolyl group, a pyrazolyl group, or a phenylgroup, any of which may be further substituted by one or more of a C₁-C₄alkyl group.
 36. The compound or a pharmaceutically acceptable saltthereof according to claim 33, wherein R² represents a cyclopropylgroup, methyl group, ethyl group, vinyl group, isopropyl group, isobutylgroup, or 2-methyl-1-propenyl group, and R³ represents a pyridyl groupor a 1-oxypyridyl group, either of which may be further substituted byone alkyl group having 1 to 4 carbon atoms or one halogen atom;pyrazolyl group; or N-methylpyrazolyl group.
 37. The compound or apharmaceutically acceptable salt thereof according to claim 33, whereinR² represents a thienyl group, a pyridyl group, a furyl group, apyrrolyl group, a pyrazolyl group, or a phenyl group, any of which maybe further substituted by one or more of an alkyl group having 1 to 4carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a chlorineatom, and R³ represents a pyridyl group or a 1-oxypyridyl group, eitherof which may be further substituted by one alkyl group having 1 to 4carbon atoms or one halogen atom; pyrazolyl group; or N-methylpyrazolylgroup.
 38. A pharmaceutical composition comprising the compound or apharmaceutically acceptable salt thereof according to any one of claims1, 2-3, 4-15, 17-20, 21-28, 29 and 31-32; and a pharmaceuticallyacceptable carrier.
 39. A compound represented by the formula (Ic):

wherein A¹ is —(CH₂)₂— or —(CH₂)₃—; A² represents a single bond orrepresents a group that links A¹ with G¹ in the form of A¹-C(═O)-G¹,A¹-C(═O)-O-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-C(═S)—NR¹⁰²-G¹, A¹-C(═NR¹⁰³)-G¹,A¹-O-G¹, A¹-O-C(═O)-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵-C(═O)-G¹,A¹-NR¹⁰⁶—S(═O)₂-G¹, A¹-NR¹⁰⁷—C(═O)O-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹,A¹—NR¹¹⁰-C(═S)-G¹, A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, A¹-S-G¹, A¹-S(═O)-G¹,A¹-S(═O)₂—NR¹¹³-G¹, A¹-CR¹¹⁴═CH-G¹, A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹, orA¹-CF═CR¹¹⁷-G¹; G¹ represents a single bond or represents a divalentgroup which is obtainable by removing two hydrogen atoms from any one ofan optionally substituted alicyclic hydrocarbon having 3 to 8 carbonatoms, an optionally substituted aromatic hydrocarbon having 6 to 14carbon atoms, and an optionally substituted heterocyclic compound having1 to 4 atoms selected from the group consisting of an oxygen atom, anitrogen atom and a sulfur atom, in the ring, A³ represents a singlebond or represents an optionally substituted divalent acyclic aliphatichydrocarbon group having 1 to 10 carbon atoms that links G¹ with A⁴ onthe same or different carbon atom; A⁴ represents a single bond orrepresents a group that links A³ with G² in the form of A³—C(═O)—O-G²,A³—C(═O)—NR¹²¹-G², A³—C(═S)—NR¹²²-G², A³—C(═NR¹²³)-G², A³-O-G²,A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G²,A³-NR¹²⁷—C(═O)—O-G², A³—NR¹²⁸—C(═O)—NR¹²⁹-G², A³-NR¹³⁰—C(═S)-G²,A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O_)-G², A³-S(═O)₂-G²,A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G²; G² is a hydrogen atom, anoptionally substituted acyclic aliphatic hydrocarbon group having 1 to10 carbon atoms, an optionally substituted alicyclic hydrocarbon grouphaving 3 to 10 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, or an optionallysubstituted heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring; A⁵ represents a single bond or —NR²⁰¹—; R² is a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an optionally substituted acyclic aliphatic hydrocarbon group having 1to 10 carbon atoms, an optionally substituted alicyclic hydrocarbongroup having 3 to 8 carbon atoms, an optionally substituted aromatichydrocarbon group having 6 to 14 carbon atoms, or an optionallysubstituted heterocyclic group having 1 to 4 atoms selected from thegroup consisting of an oxygen atom, a nitrogen atom and a sulfur atom,in the ring; A⁶ represents a single bond; R³ is an optionallysubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, oran optionally substituted heterocyclic group having 1 to 4 atomsselected from the group consisting of an oxygen atom, a nitrogen atomand a sulfur atom, in the ring; R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹²¹,R¹²², R¹²³, R¹²⁴, R¹²⁵, R¹²⁶, R¹²⁷, R¹²⁸, R¹²⁹, R¹³⁰, R¹³¹, R¹³², R¹³³,and R²⁰¹ are each independently a hydrogen atom or an aliphatichydrocarbon group having 1 to 4 carbon atoms; with the proviso that whenboth of A¹ and A³ represent an acyclic aliphatic hydrocarbon group, thenat least either one of A² or G¹ is not a single bond; and Q representsan optionally substitutedacyl group having 2 to 10 carbon atoms, anoptionally substituted alkoxymethyl group having 2 to 10 carbon atoms,or an optionally substituted benzyl group.